Chemical compounds

ABSTRACT

Pyrimidine derivatives, which are useful as VEGFR2 inhibitors are described herein. The described invention also includes methods of making such pyrimidine derivatives as well as methods of using the same in the treatment of hyperproliferative diseases.

BACKGROUND OF THE INVENTION

The present invention relates to pyrimidine derivatives, compositionsand medicaments containing the same, as well as processes for thepreparation and use of such compounds, compositions and medicaments.Such pyrimidine derivatives are useful in the treatment of diseasesassociated with inappropriate or pathological angiogenesis.

The process of angiogenesis is the development of new blood vessels fromthe pre-existing vasculature. Angiogenesis is defined herein asinvolving: (i) activation of endothelial cells; (ii) increased vascularpermeability; (iii) subsequent dissolution of the basement membrane andextravasation of plasma components leading to formation of a provisionalfibrin gel extracellular matrix; (iv) proliferation and mobilization ofendothelial cells; (v) reorganization of mobilized endothelial cells toform functional capillaries; (vi) capillary loop formation; and (vi)deposition of basement membrane and recruitment of perivascular cells tonewly formed vessels. Normal angiogenesis is active during tissue growthfrom embryonic development through maturity and then enters a period ofrelative quiescence during adulthood. Normal angiogenesis is alsoactivated during wound healing, and at certain stages of the femalereproductive cycle. Inappropriate or pathological angiogenesis has beenassociated with several disease states including various retinopathies,ischemic disease, atherosclerosis, chronic inflammatory disorders, andcancer. The role of angiogenesis in disease states is discussed, forinstance, in Fan et at, Trends in Pharmacol Sci. 16:54-66; Shawver etal, DDT Vol. 2, No. 2 February 1997; Folkmann, 1995, Nature Medicine1:27-31.

In cancer the growth of solid tumors has been shown to be dependent onangiogenesis. The progression of leukemias as well as the accumulationof fluid associated with malignant ascites and pleural effusions alsoinvolve pro-angiogenic factors. (See Folkmann, J., J. Nat'l. CancerInst., 1990, 82, 4-6.) Consequently, the targeting of pro-angiogenicpathways is a strategy being widely pursued in order to provide newtherapeutics in these areas of great, unmet medical need.

Central to the process of angiogenesis are vascular endothelial growthfactor (VEGF) and its receptors, termed vascular endothelial growthfactor receptor(s) (VEGFRs), The roles VEGF and VEGFRs play in thevascularization of solid tumors, progression of hematopoietic cancersand modulation of vascular permeability have drawn great interest in thescientific community. VEGF is a polypeptide, which has been linked toinappropriate or pathological angiogenesis (Pinedo, H. M. et al TheOncologist, Vol.5, No. 90001, 1-2, April 2000). VEGFR(s) are proteintyrosine kinases (PTKs) that catalyze the phosphorylation of specifictyrosine residues in proteins that are involved in the regulation ofcell growth, differentiation, and survival. (A. F. Wilks, Progress inGrowth Factor Research, 1990, 2, 97-111; S. A. Courtneidge, Dev. Supp.l,1993, 57-64; J. A. Cooper, Semin. Cell Biol., 1994, 5(6), 377-387; R. F.Paulson, Semin. Immunol., 1995, 7(4), 267-277; A. C. Chan, Curr. Opin.Immunol., 1996, 8(3), 394-401).

Three PTK receptors for VEGF have been identified: VEGFR1 (Fit-1);VEGFR2 (Flk-1 and KDR) and VEGFR3 (Flt-4). These receptors are involvedin angiogenesis and participate in signal transduction. (Mustonen, T. etal J. Cell Biol. 1995:129:895-898; Ferrara and Davis-Smyth, EndocrineReviews, 18(1):4-25, 1997; McMahon, G., The Oncologist, Vol. 5, No90001, 3-10, April 2000).

Of particular interest is VEGFR2, which is a transmembrane receptor PTKexpressed primarily in endothelial cells. Activation of VEGFR-2 by VEGFis a critical step in the signal transduction pathway that initiatestumor angiogenesis. VEGF expression may be constitutive to tumor cellsand can also be upregulated in response to certain stimuli. One suchstimulus is hypoxia, where VEGF expression is upregulated in both tumorand associated host tissues. The VEGF ligand activates VEGFR2 by bindingto its extracellular VEGF binding site. This leads to receptordimerization of VEGFRs and autophosphorylation of tyrosine residues atthe intracellular kinase domain of VEGFR2. The kinase domain operates totransfer a phosphate from ATP to the tyrosine residues, thus providingbinding sites for signaling proteins downstream of VEGFR-2 leadingultimately to angiogenesis. (Ferrara and Davis-Smyth, Endocrine Reviews,18(1):4-25, 1997; McMahon, G., The Oncologist, Vol. 5, No. 90001, 3-10,April 2000.)

Consequently, antagonism of the VEGFR2 kinase domain would blockphosphorylation of tyrosine residues and serve to disrupt initiation ofangiogenesis. Specifically, inhibition at the ATP binding site of theVEGFR2 kinase domain would prevent binding of ATP and preventphosphorylation of tyrosine residues. Such disruption of thepro-angiogenesis signal transduction pathway associated with VEGFR2should therefore inhibit tumor angiogenesis and thereby provide a potenttreatment for cancer or other disorders associated with inappropriateangiogenesis.

The present inventors have discovered novel pyrimidine derivativecompounds, which are inhibitors of VEGFR-2 kinase activity. Suchpyrimidine derivatives are useful in the treatment of disorders,including cancer, associated with inappropriate angiogenesis.

BRIEF SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a compound ofFormula (I):

or a salt, solvate, or physiologically functional derivative thereof:

-   wherein:-   D is-   X₁ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁-C₄ hydroxyalkyl;-   X₂ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C(O)R¹, or aralkyl;-   X₃ is hydrogen or halogen;-   X₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, heteroaralkyl,    cyanoalkyl, —(CH₂)_(p)C═CH(CH₂)_(t)H, —(CH₂)_(p)C≡C(CH₂)_(t)H, or    C₃-C₇ cycloalkyl;-   p is 1, 2, or 3;-   t is 0 or 1;-   W is N or C—R, wherein R is hydrogen, halogen, or cyano;-   Q₁ is hydrogen, halogen, C₁-C₂ haloalkyl, C₁-C₂ alkyl, C₁-C₂ alkoxy,    or C₁-C₂ haloalkoxy;-   Q₂ is A¹ or A²;-   Q₃ is A¹ when Q₂ is A² and Q₃ is A² when Q₂ is A¹;    wherein    -   A¹ is hydrogen, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, —OR′, and    -   A² is the group defined by -(Z)_(m)-(Z¹)-(Z²) wherein        -   Z is CH₂ and m is 0, 1, 2, or 3, or        -   Z is NR² and m is 0 or 1, or        -   Z is oxygen and m is 0 or 1, or        -   Z is CH₂NR² and m is 0 or 1;        -   Z¹ is S(O)₂, S(O), or C(O); and        -   Z² is C₁-C₄ alkyl, NR³R⁴, aryl, arylamino, aralkyl,            aralkoxy, or heteroaryl,-   R¹ is C₁-C₄ alkyl;-   R², R³, and R⁴ are each independently selected from hydrogen, C₁-C₄    alkyl, C₃-C₇ cycloalkyl, —S(O)₂R⁵, and —C(O)R⁵;-   R⁵ is C₁₋C₄ alkyl, or C₃₋C₇ cycloalkyl; and-   when Z is oxygen then Z¹ is S(O)₂ and when D is    then X₂ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, C(O)R¹, or aralkyl.

In a second aspect of the present invention, there is provided acompound of Formula (II):

or a salt, solvate, or physiologically functional derivative thereof:

-   wherein:-   X₁ is hydrogen, C₁-C₄ alkyl, C₁₋C₄ haloalkyl, or C₁-C₄ hydroxyalkyl;-   X₂ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C(O)R¹, or aralkyl;-   X₃ is hydrogen or halogen;-   X₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, heteroaralkyl,    cyanoalkyl, —(CH₂)_(p)C═CH(CH₂)_(t)H, —(CH₂)_(p)C≡C(CH2)_(t)H, or    C₃-C₇ cycloalkyl;-   p is 1, 2, or 3;-   t is 0 or 1;-   W is N or C—R, wherein R is hydrogen, halogen, or cyano;-   Q₁ is hydrogen, halogen, C₁-C₂ haloalkyl, C₁-C₂ alkyl, C₁-C₂ alkoxy,    or C₁-C₂ haloalkoxy;-   Q₂ is A¹ or A²;-   Q₃ is A¹ when Q₂ is A² and Q₃ is A² when Q₂ is A¹;    wherein    -   A¹ is hydrogen, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, —OR¹, and    -   A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein        -   Z is CH₂ and m is 0, 1, 2, or 3, or        -   Z is NR² and m is 0 or 1, or        -   Z is oxygen and m is 0 or 1, or        -   Z is CH₂NR² and m is 0 or 1;        -   Z¹ is S(O)₂, S(O), or C(O); and        -   Z² is C₁-C₄ alkyl, NR³R⁴, aryl, arylamino, aralkyl,            aralkoxy, or heteroaryl,-   R¹ is C₁-C₄ alkyl;-   R², R³, and R⁴ are each independently selected from hydrogen, C₁₋C₄    alkyl, C₃₋C₇ cycloalkyl, —S(O)₂R⁵, and —C(O)R⁵;-   R⁵ is C₁₋C₄ alkyl, or C₃₋C₇ cycloalkyl; and-   when Z is oxygen then Z¹ is S(O)₂.

In a third aspect of the present invention, there is provided a compoundof Formula (III):

or a salt, solvate, or physiologically functional derivative thereof:

-   wherein:-   X₁ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁₋C₄ hydroxyalkyl;-   X₂ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C(O)R¹;-   X₃ is hydrogen or halogen;-   X₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, heteroaralkyl,    cyanoalkyl, —(CH₂)_(p)C═CH(CH₂)_(t)H, —(CH₂)_(p)C≡C(CH₂)_(t)H, or    C₃-C₇ cycloalkyl;-   p is 1, 2, or 3;-   t is 0 or 1;-   W is N or C—R, wherein R is hydrogen, halogen, or cyano;-   Q₁ is hydrogen, halogen, C₁-C₂ haloalkyl, C₁-C₂ alkyl, C₁-C₂ alkoxy,    or C₁-C₂ haloalkoxy;-   Q₂ is A¹ or A²;-   Q₃ is A¹ when Q₂ is A² and Q₃ is A² when Q₂ is A¹;    wherein    -   A¹ is hydrogen, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, —OR¹, and    -   A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein        -   Z is CH₂ and m is 0, 1, 2, or 3, or        -   Z is NR² and m is 0 or 1, or        -   Z is oxygen and m is 0 or 1, or        -   Z is CH₂NR² and m is 0 or 1;        -   Z¹ is S(O)₂, S(O), or C(O); and        -   Z² is C₁₋C₄ alkyl, NR³R⁴, aryl, arylamino, aralkyl,            aralkoxy, or heteroaryl,-   R¹ is C₁-C₄ alkyl;-   R², R³, and R⁴ are each independently selected from hydrogen, C₁₋C₄    alkyl, C₃₋C₇ cycloalkyl, —S(O)₂R⁵, and —C(O)R⁵;-   R⁵ is C₁₋C₄ alkyl, or C₃₋C₇ cycloalkyl; and-   when Z is oxygen then Z¹ is S(O)₂.

In a fourth aspect of the present invention, there is provided acompound of Formula (IV):

or a salt, solvate, or physiologically functional derivative thereof:

-   wherein:-   X₁ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁₋C₄ hydroxyalkyl;-   X₂ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C(O)R¹, or aralkyl;-   X₃ is hydrogen or halogen;-   X₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, heteroaralkyl,    cyanoalkyl, —(CH₂)_(p)C═CH(CH₂)_(t)H, —(CH₂)_(p)C≡C(CH₂)_(t)H, or    C₃-C₇ cycloalkyl;-   p is 1, 2, or 3;-   t is 0 or 1;-   W is N or C—R, wherein R is hydrogen, halogen, or cyano;-   Q₁ is hydrogen, halogen, C₁-C₂ haloalkyl, C₁-C₂ alkyl, C₁-C₂ alkoxy,    or C₁-C₂ haloalkoxy;-   Q₂ is A¹ or A²;-   Q₃ is A¹ when Q₂ is A² and Q₃ is A² when Q₂ is A¹;    wherein    -   A¹ is hydrogen, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl, -OR¹, and    -   A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein        -   Z is CH₂ and m is 0, 1, 2, or 3, or        -   Z is NR² and m is 0 or 1, or        -   Z is oxygen and m is 0 or 1, or        -   Z is CH₂NR² and m is 0 or 1;        -   Z¹ is S(O)₂, S(O), or C(O); and        -   Z² is C₁₋C₄ alkyl, NR³R⁴, aryl, arylamino, aralkyl,            aralkoxy, or heteroaryl,-   R¹ is C₁-C₄ alkyl;-   R², R³, and R⁴ are each independently selected from hydrogen, C₁₋C₄    alkyl, C₃₋C₇ cycloalkyl, —S(O)₂R⁵, and —C(O)R⁵;-   R⁵ is C₁₋C₄ alkyl, or C₃₋C₇ cycloalkyl; and-   when Z is oxygen then Z¹ is S(O)₂.

In a fifth aspect of the present invention, there is provided apharmaceutical composition including a therapeutically effective amountof a compound of formula (I) or a salt, solvate, or a physiologicallyfunctional derivative thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients.

In a sixth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate VEGFR2 activity, including: administering to said mammal atherapeutically effective amount of a compound of formula (I) or a salt,solvate or a physiologically functional derivative thereof.

In a seventh aspect of the present invention, there is provided acompound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof for use in therapy.

In an eighth aspect of the present invention, there is provided the useof a compound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof in the preparation of a medicament for usein the treatment of a disorder mediated by inappropriate VEGFR2activity.

In a ninth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate VEGFR2 activity, including: administering to said mammaltherapeutically effective amounts of (i) a compound of formula (I), or asalt, solvate or physiologically functional derivative thereof and (ii)an agent to inhibit growth factor receptor function.

In an tenth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being characterized byinappropriate angiogenisis, including: administering to said mammal atherapeutically effective amount of a compound of formula (I), or asalt, solvate or physiologically functional derivative thereof.

In an eleventh aspect of the present invention, there is provided amethod of treating cancer in a mammal, including administering to saidmammal a therapeutically effective amount of a compound of formula (I),or salt, solvate or physiologically functional derivative thereof.

In a twelvth aspect of the present invention, there is provided a methodof treating cancer in a mammal, including administering to said mammaltherapeutically effective amounts of (i) a compound of formula (I), orsalt, solvate or physiologically functional derivative thereof and (ii)at least one additional anti-cancer therapy.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, mercapto, amino optionally substituted byalkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, nitro, or lower perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkyl” asused herein include, but are not limited to, n-butyl, n-pentyl,isobutyl, and isopropyl, and the like.

As used herein, the term “C₁₋C₄ alkyl” refers to an alkyl group, asdefined above, which contains at least 1, and at most 4, carbon atoms.Examples of “C₁-C₄ alkyl” groups useful in the present inventioninclude, but are not limited to, methyl, ethyl, propyl, isopropyl,isobutyl and n-butyl.

In a like manner, the terms “C₁₋C₂ alkyl” and “C₁₋C₃ alkyl” refer to analkyl group, as defined above, which contains at least 1, and at most 2and 3, carbon atoms respectively. Examples of “C₁-C₂ alkyl” and “C₁₋C₃alkyl” groups useful in the present invention include, methyl, ethyl,n-propyl and isopropyl.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the group whichincludes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, n-propylene,n-butylene, and the like.

As used herein, the terms “C₁₋C₃ alkylene” and “C₁₋C₄ alkylene” refer toan alkylene group, as defined above, which contains at least 1, and atmost 3 or 4, carbon atoms respectively. Examples of “C₁₋C₃ alkylene”groups useful in the present invention include, but are not limited to,methylene, ethylene, and n-propylene.

As used herein, the terms “halogen” or “halo” refer to fluoro (—F),chloro (—Cl), bromo (—Br), or iodo (—I).

As used herein, the term “C₁₋C₄ haloalkyl” refers to a straight orbranched chain hydrocarbon containing at least 1, and at most 4, carbonatoms substituted with at least one halogen, halogen being as definedherein. Examples of branched or straight chained “C₁₋C₄ haloalkyl”groups useful in the present invention include, but are not limited to,methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substitutedindependently with one or more halogens, e.g., fluoro, chloro, bromo andiodo.

In a like manner, the terms “C₁₋C₂ haloalkyl” and “C₁₋C₃ haloalkyl”refer to a straight or branched chain hydrocarbon containing at least 1,and at most 2 and 3, carbon atoms respectively substituted with at leastone halogen, halogen being as defined herein. Examples of branched orstraight chained “C₁₋C₂ haloalkyl” and “C₁₋C₃ haloalkyl” groups usefulin the present invention include, but are not limited to, methyl, ethyl,n-propyl, and isopropyl substituted independently with one or morehalogens, e.g., fluoro, chloro, bromo and iodo.

As used herein, the term “hydroxy” refers to the group —OH.

As used herein, the term “C₁₋C₄ hydroxyalkyl” refers to a straight orbranched chain hydrocarbon containing at least 1, and at most 4, carbonatoms substituted with at least one hydroxy, hydroxy being as definedherein. Examples of branched or straight chained “C₁₋C₄ hydroxyalkyl”groups useful in the present invention include, but are not limited to,methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substitutedindependently with one or more hydroxy groups.

As used herein, the term “C₃₋C₇ cycloalkyl” refers to a non-aromaticcyclic hydrocarbon ring having from three to seven carbon atoms, whichoptionally includes a C₁-C₄ alkylene linker through which it may beattached. Exemplary “C₃-C₇ cycloalkyl” groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered non-aromatic ring being unsaturatedor having one or more degrees of unsaturation containing one or moreheteroatomic substitutions selected from S, SO, SO₂, O, or N, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or lower perfluoroalkyl, multiple degrees of substitution beingallowed. Such a ring may be optionally fused to one or more of another“heterocyclic” ring(s) or cycloalkyl ring(s). Examples of “heterocyclic”include, but are not limited to, tetrahydrofuran, pyran, 1,4-dioxane,1,3-dioxane, piperidine, pyrrolidine, morpholine, tetrahydrothiopyran,tetrahydrothiophene, and the like.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted benzene ring system fusedto one or more optionally substituted benzene rings to form, forexample, anthracene, phenanthrene, or napthalene ring systems. Exemplaryoptional substituents include lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, tetrazolyl,carbamoyl optionally substituted by alkyl, aminosulfonyl optionallysubstituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy, aroyloxy,heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerperfluoroalkyl, heteroaryl, or aryl, multiple degrees of substitutionbeing allowed. Examples of “aryl” groups include, but are not limitedto, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, as well as substitutedderivatives thereof.

As used herein, the term “aralkyl” refers to an aryl or heteroarylgroup, as defined herein including both unsubstituted and substitutedversions thereof, attached through a lower alkylene linker, whereinlower alkylene is as defined herein. As used herein, the term“heteroaralkyl” is included within the scope of the term “aralkyl”. Theterm heteroaralkyl is defined as a heteroaryl group, as defined herein,attached through a lower alkylene linker, lower alkylene is as definedherein. Examples of “aralkyl”, including “heteroaralkyl”, include, butare not limited to, benzyl, phenylpropyl, 2-pyridinylmethyl,4-pyridinylmethyl, 3-isoxazolylmethyl, 5-methyl-3-isoxazolylmethyl, and2-imidazoyly ethyl.

As used herein, the term “arylamino” refers to an aryl or heteroarylgroup, as defined herein, attached through an amino group —NR²—, whereinR² is as defined herein.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic aromatic ringsystem comprising two of such monocyclic five to seven membered aromaticrings. These heteroaryl rings contain one or more nitrogen, sulfur,and/or oxygen heteroatoms, where N-oxides and sulfur oxides and dioxidesare permissible heteroatom substitutions and may be optionallysubstituted with up to three members selected from a group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, tetrazolyl, carbamoyl optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, lower perfluoroalkyl, heteroaryl,or aryl, multiple degrees of substitution being allowed. Examples of“heteroaryl” groups used herein include furan, thiophene, pyrrole,imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole,oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine,pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole,indazole, and substituted versions thereof.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl as defined above and the term “C₁₋C₂ alkoxy” refers tothe group R_(a)O—, where R_(a) is C₁₋C₂ alkyl as defined above.

As used herein, the term “haloalkoxy” refers to the group R_(a)O—, whereR_(a) is haloalkyl as defined above and the term “C₁₋C₂ haloalkoxy”refers to the group R_(a)O—, where R_(a) is C₁₋C₂ halolkyl as definedabove.

As used herein the term “aralkoxy” refers to the group R_(b)R_(a)O—,where R_(a) is alkylene and R_(b) is aryl, both as defined above.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl as defined above.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl as defined above.

As used herein, the term “alkylsulfonyl” refers to the group R_(a)SO₂—,where R_(a) is alkyl as defined above.

As used herein, the term “oxo” refers to the group ═O

As used herein, the term “mercapto” refers to the group —SH.

As used herein, the term “carboxy” refers to the group —COOH.

As used herein, the term “cyano” refers to the group —CN.

As used herein the term “cyanoalkyl” refers to the group —R_(a)CNwherein R_(a) is C₁-C₃ alkylene as defined above. Exemplary “cyanoalkyl”groups useful in the present invention include, but are not limited to,cyanomethyl, cyanoethyl, and cyanopropyl.

As used herein, the term “aminosulfonyl” refers to the group —SO₂NH₂.

As used herein, the term “carbamoyl” refers to the group —C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the group —S—.

As used herein, the term “sulfenyl” shall refer to the group —S(O)—.

As used herein, the term “sulfonyl” shall refer to the group —S(O)₂— or—SO₂— or —S(O₂).

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl as defined herein.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl as defined herein.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl as defined herein.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” refers to the groupR_(a)C(O)O—, where R_(a) is heteroaryl as defined herein.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s),which occur, and events that do not occur.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I), (II), (III), or (IV) or a salt or physiologicallyfunctional derivative thereof) and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include, but are notlimited to, water, methanol, ethanol and acetic acid. Preferably thesolvent used is a pharmaceutically acceptable solvent. Examples ofsuitable pharmaceutically acceptable solvents include water, ethanol andacetic acid. Most preferably the solvent used is water.

The compounds of formulae (I), (II), (III), or (IV) may have the abilityto crystallize in more than one form, a characteristic, which is knownas polymorphism, and it is understood that such polymorphic forms(“polymorphs”) are within the scope of formulae (I), (II), (III), and(IV). Polymorphism generally can occur as a response to changes intemperature or pressure or both and can also result from variations inthe crystallization process. Polymorphs can be distinguished by variousphysical characteristics known in the art such as x-ray diffractionpatterns, solubility, and melting point.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Certain of the compounds described herein may contain one or more chiralatoms, or may otherwise be capable of existing as two enantiomers.Accordingly, the compounds of this invention include mixtures ofenantiomers as well as purified enantiomers or enantiomerically enrichedmixtures. Also included within the scope of the invention are theindividual isomers of the compounds represented by formula (I), (II),(III), and (IV) above as well as any wholly or partially equilibratedmixtures thereof. The present invention also covers the individualisomers of the compounds represented by the formulas above as mixtureswith isomers thereof in which one or more chiral centers are inverted.

It is also noted that the compounds of Formula (I), (II), (III), or (IV)may form tautomers. It is understood that all tautomers and mixtures oftautomers of the compounds of the present invention, more specifically,the compounds of formula (III) are included within the scope of thecompounds of the present invention, including the compounds of formula(III).

It is to be understood that the following embodiments refer to compoundswithin the scope of all of formula (I), formula (II), formula (III), andformula (IV) as defined above except as specifically limited by thedefinition of each formula or specifically limited otherwise. It is alsounderstood that the embodiments of the present invention describedherein, including uses and compositions, are applicable to all offormula (I), (II), (III), and (IV).

In one embodiment D is:

In another embodiment, D is:

In a further embodiment, D is

It is understood that D is attached to the indicated nitrogen of Formula(I) through the bond of D having an unfilled valence and being indicatedby “\”. The appropriate attachment is further illustrated in Formulae(II), (III), or (IV) and in the working examples recited below.

In one embodiment, X₁ is hydrogen or C₁₋₄ alkyl. In a preferredembodiment, X₁ is methyl or ethyl. In a more preferred embodiment, X₁ ismethyl.

In one embodiment, X₂ is hydrogen or C₁₋₄ alkyl. In a preferredembodiment, X₂ is hydrogen or methyl. In a more preferred embodiment, X₂is hydrogen. In another preferred embodiment, X₂ is methyl.

In one embodiment, X₃ is halogen. In a preferred embodiment, X₃ ishydrogen.

In one embodiment, X₄ is hydrogen, C₁-C₄ alkyl, cyanoalkyl, or—(CH₂)_(p)C=C(CH₂)_(t)H. In a preferred embodiment, X₄ is hydrogen,methyl, ethyl, isopropyl, cyanomethyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H,wherein p is 1 and t is 0. In a more preferred embodiment, X₄ is methyl.

In one embodiment, X₁ is methyl or ethyl, X₂ is hydrogen or methyl, X₃is hydrogen or halogen, and X₄ is hydrogen, methyl, ethyl, isopropyl,cyanomethyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H, wherein p is 1 and t is 0. In apreferred embodiment, X₁ is methyl, X₂ is hydrogen, X₃ is hydrogen, andX₄ is methyl. In another preferred embodiment, X₁ is methyl, X₂ ismethyl, X₃ is hydrogen, and X₄ is methyl.

In a preferred embodiment, D is:

and X₁ is methyl, X₂ is hydrogen, X₃ is hydrogen, and X₄ is methyl.

In another preferred embodiment, D is

and X₁ is methyl, X₂ is methyl, X₃ is hydrogen, and X₄ is methyl.

In one embodiment, W is N. In another embodiment W is C—R wherein R isH, F, or Cl. In a preferred embodiment, W is N, C—H, C—F, or C—CN. In amore preferred embodiment, W is C—F or C—H. In a most preferredembodiment, W is C—H.

In another embodiment, Q₁ is hydrogen, halogen, C₁-C₂ alkyl or C₁-C₂alkoxy. In a preferred embodiment, Q₁ is hydrogen, chlorine, methyl, ormethoxy.

In one embodiment, Q₂ is A¹ and Q₃ is A². In an alternative embodiment,Q₂ is A² and Q₃ is A¹.

In one embodiment, Q₂ is A² and Q₃ is A¹, wherein A¹ is hydrogen,halogen, or C₁₋C₃ haloalkyl and A² is the group defined by-(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z isNR²and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂, S(O),or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴ and wherein R², R³, and R⁴ areeach independently selected from H or C₁₋C₄ alkyl. In a preferredembodiment, Q₂ is A²and Q₃ is A¹, wherein A¹ is hydrogen or chlorine andA² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is0, 1, 2, or 3; Z¹ is S(O)₂; and Z² is C₁₋C₄ alkyl.

In one embodiment, Q₂ is A¹ and Q₃ is A², wherein A¹ is hydrogen,halogen, or C₁₋C₃ alkyl and A² is the group defined by-(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z is NR²and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂, S(O), orC(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R², R³, and R⁴ areeach independently selected from H or C₁₋C₄ alkyl. In a preferredembodiment, Q₂ is A¹ and Q₃ is A², wherein A¹ is hydrogen, methyl, orchlorine and A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z isCH₂ and m is 0, 1, 2, or 3; Z¹ is S(O)₂; and Z² is C₁₋C₄ alkyl or NR³R⁴,wherein R³ and R⁴ are each independently selected from hydrogen or C₁₋C₄alkyl.

In one embodiment, X₁ is hydrogen or C₁₋₄ alkyl; X₂ is hydrogen or C₁₋₄alkyl; X₃ is hydrogen or halogen; and X₄ is hydrogen, C₁-C₄ alkyl,cyanoalkyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H; W is N; Q₁ is hydrogen, halogen,C₁₋C₂ alkyl or C₁₋C₂ alkoxy; and Q₂ is A² and Q₃ is A¹, wherein A¹ ishydrogen, halogen, or C₁₋C₃ haloalkyl and A² is the group defined by-(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z is NR²and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂ or C(O);and Z² is C₁₋C₄ alkyl or NR³R⁴ and wherein R², R³, and R⁴ are eachindependently selected from hydrogen or C₁₋C₄ alkyl.

In one embodiment, X₁ is hydrogen or C₁₋₄ alkyl; X₂ is hydrogen or C₁₋₄alkyl; X₃ is hydrogen or halogen; and X₄ is hydrogen, C₁-C₄ alkyl,cyanoalkyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H; W is C—R wherein R is H, F, Cl,or CN; Q₁ is hydrogen, halogen, C₁₋C₂ alkyl or C₁₋C₂ alkoxy; and Q₂ isA² and Q₃ is A¹ , wherein A¹ is hydrogen, halogen, or C₁₋C₃ haloalkyland A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ andm is 0, 1, 2, or 3, or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is0 or 1; Z¹ is S(O)₂ or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴and whereinR², R³, and R⁴ are each independently selected from hydrogen orC₁₋C₄alkyl.

In one embodiment, X₁ is hydrogen or C₁₋₄ alkyl; X₂ is hydrogen or C₁₋₄alkyl; X₃ is hydrogen or halogen; and X₄ is hydrogen, C₁-C₄ alkyl,cyanoalkyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H; W is N; Q, is hydrogen, halogen,C₁₋C₂ alkyl or C₁₋C₂ alkoxy; Q₂ is A¹ and Q₃ is A², wherein A¹ ishydrogen, halogen, or C₁₋C₃ alkyl and A² is the group defined by(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z is NR²and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂, S(O), orC(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R², R³, and R⁴ areeach independently selected from hydrogen or C₁₋C₄ alkyl.

In one embodiment, X₁ is hydrogen or C₁₋₄ alkyl; X₂ is hydrogen or C₁₋₄alkyl; X₃ is hydrogen or halogen; and X₄ is hydrogen, C₁-C₄ alkyl,cyanoalkyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H; W is C—R wherein R is H, F, Cl,or CN; Q₁ is hydrogen, halogen, C₁₋C₂ alkyl or C₁-C₂ alkoxy; Q₂ is A¹and Q₃ is A², wherein A¹ is hydrogen, halogen, or C₁₋C₃ alkyl and A² isthe group defined by -(Z)_(m)-(Zi)-(Z²), wherein Z is CH₂ and m is 0, 1,2, or 3, or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹is S(O)₂, S(O), or C(O); and Z² is C₁-C₄ alkyl or NR³R⁴, and wherein R²,R³, and R⁴ are each independently selected from hydrogen or C₁₋C₄ alkyl.

In one embodiment, X₁ is methyl or ethyl; X₂ is hydrogen or methyl; X₃is hydrogen; and X₄ is hydrogen, methyl, ethyl, isopropyl, cyanomethyl,or —(CH₂)_(p)C≡C(CH₂)_(t)H, wherein p is 1 and t is 0.; W is N, C—H,C—F, C—CN; Q₁ is hydrogen, chlorine, or methoxy; Q₂ is A¹ and Q₃ is A² ,wherein A¹ is hydrogen, methyl, or chlorine and A² is the group definedby -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z isNR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂, S(O),or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R² R³, and R⁴ areeach independently selected from hydrogen or C₁₋C₄ alkyl.

In one embodiment, X₁ is methyl or ethyl; X₂ is hydrogen or methyl; X₃is hydrogen; and X₄ is hydrogen, methyl, ethyl, isopropyl, cyanomethyl,or —(CH₂)_(p)C≡C(CH₂)_(t)H, wherein p is 1 and t is 0.; W is C—H or C—F;Q₁ is hydrogen, chlorine, methyl, or methoxy; Q₂ is A¹ and Q₃ is A² ,wherein A¹ is hydrogen, methyl, or chlorine and A² is the group definedby -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z isNR²and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂, S(O),or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R², R³, and R⁴ areeach independently selected from hydrogen or C₁₋C₄ alkyl.

In one embodiment, X₁ is methyl; X₂ is hydrogen; X₃ is hydrogen; and X₄is methyl; W is C—H; Q₁ is hydrogen, methyl, chlorine, or methoxy; Q₂ isA¹ and Q₃ is A², wherein A¹ is hydrogen, methyl, or chlorine and A² isthe group defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1,2, or 3, or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹is S(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R²,R³, and R⁴ are each independently selected from hydrogen or C₁₋C₄ alkyl.

In a preferred embodiment, D is:

and X₁ is methyl; X₂ is hydrogen; X₃ is hydrogen; and X₄ is methyl; W isC—H; Q₁ is hydrogen, methyl, chlorine, or methoxy; Q₂ is A¹ and Q₃ is A², wherein A¹ is hydrogen, methyl, or chlorine and A² is the groupdefined by -(Z^(m)-(Z^(l))-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or3, or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ isS(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R²,R³, and R⁴ are each independently selected from hydrogen or C₁₋C₄ alkyl.

In one embodiment, X₁ is methyl; X₂ is methyl; X₃ is hydrogen; and X₄ ismethyl; W is C—H; Q₁ is hydrogen, chlorine, methyl, or methoxy; Q₂ is A¹and Q₃ is A², wherein A¹ is hydrogen, methyl, or chlorine and A² is thegroup defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2,or 3, or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ isS(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R²,R³, and R⁴ are each independently selected from hydrogen or C₁₋C₄ alkyl.

In another preferred embodiment, D is

and X₁ is methyl; X₂ is methyl; X₃ is hydrogen; and X₄ is methyl; W isC—H; Q, is hydrogen, chlorine, methyl, or methoxy; Q₂ is A¹ and Q₃ is A², wherein A¹ is hydrogen, methyl, or chlorine and A² is the groupdefined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3,or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ isS(O)2, S(O), or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R²,R³, and R⁴ are each independently selected from hydrogen or C₁₋C₄ alkyl.

In one embodiment, X₁ is methyl; X₂ is hydrogen; X₃ is hydrogen; and X₄is methyl; W is C—F; Q₁ is hydrogen, chlorine, or methoxy; Q₂ is A¹ andQ₃ is A², wherein A¹ is hydrogen, methyl, or chlorine and A² is thegroup defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2,or 3, or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ isS(O)₂, S(O), or C(O); and Z² is C₁₋C₄alkyl or NR³R⁴, and wherein R², R³,and R⁴ are each independently selected from hydrogen or C₁₋C₄alkyl.

Specific examples of compounds of the present invention include thefollowing:

-   N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-5-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-4-methoxy-N-methylbenzenesulfonamide;-   5-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;-   3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-N-isopropylbenzenesulfonamide;-   5-fluoro-N²-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N-[5-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-2-methylphenyl]methanesulfonamide;-   5-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-[4-(methylsulfonyl)phenyl]-2,4-pyrimidinediamine;-   N⁴-(3-ethyl-1H-indazol-6-yl)-5-fluoro-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;-   4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   N⁴-ethyl-5-fluoro-N²-[2-methoxy-5-(methylsulfonyl)phenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   [4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]-N-methylmethanesulfonamide;-   5-fluoro-N²-{3-[(isopropylsulfonyl)methyl]phenyl}-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino)-2-pyrimidinyl}amino)-4-methoxybenzamide;-   4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-3-methoxybenzenesulfonamide;-   N²-(3-methyl-1H-indazol-6-yl)-N⁴-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diamine    trifluoroacetate;-   N²-methyl-N²-(3-methyl-1H-indazol-6-yl)-N⁴-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diamine;-   N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine;-   N-[2-methyl-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-1,3,5-triazin-2-yl}amino)phenyl]methanesulfonamide;-   N²-methyl-N²-(3-methyl-1H-indazol-6-yl)-N⁴-[3-(methylsulfonyl)phenyl]-1,3,5-triazine-2,4-diamine;-   N-[4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-1,3,5-triazin-2-yl}amino)phenyl]acetamide;-   3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;-   N-isopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   N-cyclopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   N⁴-ethyl-N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]methanesulfonamide;-   N²-{3-[(isopropylsulfonyl)methyl]phenyl}-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N²-{4-[(isopropylsulfonyl)methyl]phenyl}-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N²-[5-(isobutylsulfonyl)-2-methoxyphenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]acetamide;-   N-3-({4-[ethyl(3-methyl-1h-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]acetamide;-   N²-(2-methoxy-5-{[(5-methyl-3-isoxazolyl)methyl]sulfonyl}phenyl)-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   4-methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   N²-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-isopropyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N⁴-(1H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;-   N⁴-(1,3-dimethyl-1H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;-   N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;-   N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-2,4-pyrimidinediamine;-   1-[4-methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]-1-propanone;-   4-methoxy-N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]benzenesulfonamide;-   4-methoxy-N-methyl-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   [(3-methyl-1H-indazol-6-yl)(2-{4-[(methylsulfonyl)methylanilino}-4-pyrimidinyl)amino]acetonitrile;-   [{2-[5-(ethylsulfonyl)-2-methoxyanilino]-4-pyrimidinyl}(3-methyl-1H-indazol-6-yl)amino]acetonitrile;-   [(3-methyl-1H-indazol-6-yl)(2-{3-[(methylsulfonyl)methyl]anilino}-4-pyrimidinyl)amino]acetonitrile;-   4-methoxy-N-methyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzamide;-   3-methoxy-4-({4-[methyl(3-methyl-12H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   N⁴-ethynyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;-   3-({4-[(3-methyl-1H-indazol-6-yl)(2-propynyl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-[3-(methylsulfonyl)phenyl]-2,4-pyrimidinediamine;-   4-methoxy-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzamide;-   N²-[4-(ethylsulfonyl)phenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N-[4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzyl]ethanesulfonamide;-   N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzyl]methanesulfonamide;-   2-chloro-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   2-chloro-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   4-chloro-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   3-methyl-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   2-methyl-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   4-methyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;-   N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-[3-(methylsulfinyl)phenyl]-2,4-pyrimidinediamine;-   N²-[2-fluoro-5-(methylsulfonyl)phenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   N²-[2-methoxy-5-(methylsulfonyl)phenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;-   5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide;-   3-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;-   2-[4-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)phenyl]ethanesulfonamide;-   N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-N²-{4-[(methylsulfonyl)methyl]phenyl}pyrimidine-2,4-diamine;-   3-({4-([3-(hydroxymethyl)-2-methyl-2H-indazol-6-yl](methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;-   3-({4-[(1,2-dimethyl-1H-benzimidazol-5-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;-   3-({4-[(2-benzyl-1-methyl-1H-benzimidazol-5-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;-   3-({4-[(2-ethyl-3-methyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;-   3-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;-   3-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-1,3,5-triazin-2-yl}amino)benzenesulfonamide;    and-   5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-1,3,5-triazin-2-yl}amino)-2-methylbenzenesulfonamide;-   or a salt, solvate, or physiologically functional derivative    thereof.

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention. Salts of the compounds of the present invention may compriseacid addition salts derived from a nitrogen on a substituent in thecompound of formula (I). Representative salts include the followingsalts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxyna phthoate, iodide, isethionate, lactate,lactobionate, ia u rate, ma late, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, potassium, salicylate, sodium, stearate, subacetate,succinate, tannate, tartrate, teociate, tosylate, triethiodide,trimethylammonium and valerate. Other salts, which are notpharmaceutically acceptable, may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as salts, solvates andphysiological functional derivatives thereof, may be administered as theraw chemical, it is possible to present the active ingredient as apharmaceutical composition. Accordingly, the invention further providespharmaceutical compositions, which include therapeutically effectiveamounts of compounds of the formula (I) and salts, solvates andphysiological functional derivatives thereof, and one or morepharmaceutically acceptable carriers, diluents, or excipients. Thecompounds of the formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are as described above. The carrier(s),diluent(s) or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical formulation including admixing a compound of theformula (I), or salts, solvates and physiological functional derivativesthereof, with one or more pharmaceutically acceptable carriers, diluentsor excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, of a compound of the formula (I) depending on the conditionbeing treated, the route of administration and the age, weight andcondition of the patient. Preferred unit dosage formulations are thosecontaining a daily dose or sub-dose, as herein above recited, or anappropriate fraction thereof, of an active ingredient. Furthermore, suchpharmaceutical formulations may be prepared by any of the methods wellknown in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additives suchas peppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian. However, an effective amount of acompound of formula (I) for the treatment of neoplastic growth, forexample colon or breast carcinoma, will generally be in the range of 0.1to 100 mg/kg body weight of recipient (mammal) per day and more usuallyin the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kgadult mammal, the actual amount per day would usually be from 70 to 700mg and this amount may be given in a single dose per day or more usuallyin a number (such as two, three, four, five or six) of sub-doses per daysuch that the total daily dose is the same. An effective amount of asalt or solvate, or physiologically functional derivative thereof, maybe determined as a proportion of the effective amount of the compound offormula (I) per se. It is envisaged that similar dosages would beappropriate for treatment of the other conditions referred to above.

The compounds of the present invention and their salts and solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in anti-cancer therapy,combination with other chemotherapeutic, hormonal or antibody agents isenvisaged as well as combination with surgical therapy and radiotherapy.Combination therapies according to the present invention thus comprisethe administration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof, and the use of at leastone other cancer treatment method. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one compound of formula (I) or a pharmaceutically acceptable saltor solvate thereof, or a physiologically functional derivative thereof,and at least one other pharmaceutically active agent, preferably ananti-neoplastic agent. The compound(s) of formula (I) and the otherpharmaceutically active agent(s) may be administered together orseparately and, when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

The compounds of the Formula (I) or salts, solvates, or physiologicallyfunctional derivatives thereof and at least one additional cancertreatment therapy may be employed in combination concomitantly orsequentially in any therapeutically appropriate combination with suchother anti-cancer therapies. In one embodiment, the other anti-cancertherapy is at least one additional chemotherapeutic therapy includingadministration of at least one anti-neoplastic agent. The administrationin combination of a compound of formula (I) or salts, solvates, orphysiologically functional derivatives thereof with otheranti-neoplastic agents may be in combination in accordance with theinvention by administration concomitantly in (1) a unitarypharmaceutical composition including both compounds or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one anti-neoplastic agent is administeredfirst and the other second or vice versa. Such sequential administrationmay be close in time or remote in time.

Anti-neoplastic agents may induce anti-neoplastic effects in acell-cycle specific manner, i.e., are phase specific and act at aspecific phase of the cell cycle, or bind DNA and act in a noncell-cycle specific manner, i.e., are non-cell cycle specific andoperate by other mechanisms.

Anti-neoplastic agents useful in combination with the compounds andsalts, solvates or physiologically functional derivatives thereof offormula I include the following:

(1) cell cycle specific anti-neoplastic agents including, but notlimited to, diterpenoids such as paclitaxel and its analog docetaxel;vinca alkaloids such as vinblastine, vincristine, vindesine, andvinorelbine; epipodophyllotoxins such as etoposide and teniposide;fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine;antimetabolites such as allopurinol, fludurabine, methotrexate,cladrabine, cytarabine, mercaptopurine and thioguanine; andcamptothecins such as 9-amino camptothecin, irinotecan, CPT-11 and thevarious optical forms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;

(2) cytotoxic chemotherapeutic agents including, but not limited to,alkylating agents such as melphalan, chlorambucil, cyclophosphamide,mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine,and dacarbazine; anti-tumour antibiotics such as doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dacttinomycin andmithramycin; and platinum coordination complexes such as cisplatin,carboplatin, and oxaliplatin; and

(3) other chemotherapeutic agents including, but not limited to,anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifeneand iodoxyfene; progestrogens such as megestrol acetate; aromataseinhibitors such as anastrozole, letrazole, vorazole, and exemestane;antiandrogens such as flutamide, nilutamide, bicalutamide, andcyproterone acetate; LHRH agonists and antagagonists such as goserelinacetate and luprolide, testosterone 5α-dihydroreductase inhibitors suchas finasteride; metalloproteinase inhibitors such as marimastat;antiprogestogens; urokinase plasminogen activator receptor functioninhibitors; cyclooxygenase type 2 (COX-2) inhibitors such as celecoxib;other angiogenic inhibiting agents such as VEGFR inhibitors other thanthose described herein and TIE-2 inhibitors; growth factor functioninhibitors such as inhibitors of the functions of hepatocyte growthfactor; erb-B2, erb-B4, epidermal growth factor receptor (EGFr),platelet derived growth factor receptor (PDGFr), vascular endothelialgrowth factor receptor (VEGFR) other than those described in the presentinvention, and TIE-2; and other tyrosine kinase inhibitors such ascyclin dependent inhibitors such as CDK2 and CDK4 inhibitors.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are believed to have anticancer activityas a result of inhibition of the protein kinase VEGFR2 and its effect onselected cell lines whose growth is dependent on VEGFR2 protein kinaseactivity.

The present invention thus also provides compounds of formula (I) andpharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders mediated byinappropriate VEGFR2 activity.

The inappropriate VEGFR2 activity referred to herein is any VEGFR2activity that deviates from the normal VEGFR2 activity expected in aparticular mammalian subject. Inappropriate VEGFR2 activity may take theform of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of VEGFR2 activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of the protein kinase or ligand leading to inappropriate oruncontrolled activation of the receptor. Furthermore, it is alsounderstood that unwanted VEGFR2 activity may reside in an abnormalsource, such as a malignancy. That is, the level of VEGFR2 activity doesnot have to be abnormal to be considered inappropriate, rather theactivity derives from an abnormal source. In a like manner, theinappropriate angiogenesis referred to herein is any angiogenic activitythat deviates from the normal angiogenic activity expected in aparticular mammalian subject. Inappropriate angiogenesis may take theform of, for instance, an abnormal increase in activity, or anaberration in the timing and or control of angiogenic activity. Suchinappropriate activity may result then, for example, from overexpressionor mutation of a protein kinase or ligand leading to inappropriate oruncontrolled activation of angiogenesis. Furthermore, it is alsounderstood that unwanted angiogenic activity may reside in an abnormalsource, such as a malignancy. That is, the level of angiogenic activitydoes not have to be abnormal to be considered inappropriate, rather theactivity derives from an abnormal source.

The present invention is directed to methods of regulating, modulating,or inhibiting VEGFR2 for the prevention and/or treatment of disordersrelated to unregulated VEGFR2 activity. In particular, the compounds ofthe present invention can also be used in the treatment of certain formsof cancer. Furthermore, the compounds of the present invention can beused to provide additive or synergistic effects with certain existingcancer chemotherapies and radiation, and/or be used to restoreeffectiveness of certain existing cancer chemotherapies and radiation.

The compounds of the present invention are also useful in the treatmentof one or more diseases afflicting mammals which are characterized bycellular proliferation in the area of disorders associated withneo-vascularization and/or vascular permeability including blood vesselproliferative disorders including arthritis and restenosis; fibroticdisorders including hepatic cirrhosis and atherosclerosis; mesangialcell proliferative disorders include glomerulonephritis, diabeticnephropathy, malignant nephroscierosis, thrombotic microangiopathysyndromes, proliferative retinopathies, organ transplant rejection andglomerulopathies; and metabolic disorders include psoriasis, diabetesmellitus, chronic wound healing, inflammation and neurodegenerativediseases.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder mediated by inappropriate VEGFR2activity, including susceptible malignancies, which includesadministering to said subject an effective amount of a compound offormula (I) or a pharmaceutically acceptable salt, solvate, or aphysiologically functional derivative thereof. In a preferredembodiment, the disorder is cancer.

A further aspect of the invention provides a method of treatment of amammal suffering from cancer, which includes administering to saidsubject an effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of a disordercharacterized by inappropriate VEGFR2 activity. In a preferredembodiment, the disorder is cancer.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of cancer and malignanttumours.

The mammal requiring treatment with a compound of the present inventionis typically a human being.

In another embodiment, therapeutically effective amounts of thecompounds of formula (I) or salts, solvates or physiologically derivedderivatives thereof and agents which inhibit growth factor receptorfunction may be administered in combination to a mammal for treatment ofa disorder mediated by inappropriate VEGFR2 activity, for instance inthe treatment of cancer. Such growth factor receptors include, forexample, EGFR, PDGFR, erbB2, erbB4, VEGFR, and/or TIE-2. Growth factorreceptors and agents that inhibit growth factor receptor function aredescribed, for instance, in Kath, John C., Exp. Opin. Ther. Patents(2000) 10(6):803-818 and in Shawver et al DDT Vol 2, No. 2 February1997.

The compounds of the Formula (I) or salts, solvates, or physiologicallyfunctional derivatives thereof and the agent for inhibiting growthfactor receptor function may be employed in combination concomitantly orsequentially in any therapeutically appropriate combination. Thecombination may be employed in combination in accordance with theinvention by administration concomitantly in (1) a unitarypharmaceutical composition including both compounds or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one is administered first and the other secondor vice versa. Such sequential administration may be close in time orremote in time.

In another aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate angiogenesis, including: administering to said mammal atherapeutically effective amount of a compound of formula (I), or asalt, solvate or physiologically functional derivative thereof. In oneembodiment, the inappropriate angiogenic activity is due to at least oneof inappropriate VEGFR1, VEGFR2, VEGFR3, or TIE-2 activity. In anotherembodiment, the inappropriate angiogenesis is due to inappropriateVEGFR2 and TIE-2 activity. In a further embodiment, the method furtherincludes administering a therapeutically effective amount of a TIE-2inhibitor along with the compounds of formula (I) or salts, solvates orphysiologically functional derivatives thereof. Preferably the disorderis cancer.

In another aspect of the present invention, there is provided the use ofa compound of formula (I), or a salt, solvate or physiologicallyfunctional derivative thereof in the preparation of a medicament for usein treating a disorder in a mammal, said disorder being characterized byinappropriate angiogenesis. In one embodiment, the inappropriateangiogenic activity is due to at least one of inappropriate VEGFR1,VEGFR2, VEGFR3 or TIE-2 activity. In another embodiment, theinappropriate angiogenic activity is due to inappropriate VEGFR2 andME-2 activity. In a further embodiment, the use further includes use ofa TIE-2 inhibitor to prepare said medicament.

The combination of a compound of formula (I) or salts, solvates, orphysiologically functional derivatives with a TIE-2 inhibitor may beemployed in combination in accordance with the invention byadministration concomitantly in (1) a unitary pharmaceutical compositionincluding both compounds or (2) separate pharmaceutical compositionseach including one of the compounds. Alternatively, the combination maybe administered separately in a sequential manner wherein one isadministered first and the other second or vice versa. Such sequentialadministration may be close in time or remote in time.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

Compounds of general formula (I), (II), (III), and (IV) may be preparedby methods known in the art of organic synthesis as set forth in part bythe following synthesis schemes. Generally, the following schemes areillustrated using compounds of formula (II), but it is recognized thatsuch schemes are easily adaptable by the skilled artisan to preparecompounds of formula (I), including compounds of formula (III) and (IV).It is also recognized that in all of the schemes described below, it iswell understood that protecting groups for sensitive or reactive groupsare employed where necessary in accordance with general principles ofchemistry. Protecting groups are manipulated according to standardmethods of organic synthesis (T. W. Green and P. G. M. Wuts (1991)Protecting Groups in Organic Synthesis, John Wiley & Sons). These groupsare removed at a convenient stage of the compound synthesis usingmethods that are readily apparent to those skilled in the art. Theselection of processes as well as the reaction conditions and order oftheir execution shall be consistent with the preparation of compounds offormula (I). Those skilled in the art will recognize if a stereocenterexists in compounds of formula (I). Accordingly, the present inventionincludes both possible stereoisomers and includes not only racemiccompounds but the individual enantiomers as well. When a compound isdesired as a single enantiomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be effected by any suitable method known in theart. See, for example, Stereochemistry of Organic Compounds by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

Compounds of formula (II), wherein W is C—H, can be prepared accordingto the synthetic sequence shown in Scheme 1 and further detailed in theExamples section following. Typically 2,4-Dichloropyrimidine (I)undergoes a displacement reaction at C4 with an appropriateaminoindazole (A) to provide the 2-chloro-4-arylaminopyrimidinederivative (B). For compounds of formula (II), wherein X₄ is hydrogen, afurther displacement at C2 is carried out with an appropriate arylamine(C) to provide the compound of Formula (II), wherein X₄ is hydrogen.Alternatively, for compounds of Formula (II), wherein X₄ is nothydrogen, chloropyrimidine B is treated with di-t-butyl-dicarbonate toaffect BOC protection at N1 of the indazole (Scheme 2). SubsequentN-alkylation under standard conditions affords theN⁴-alkyl-2-chloropyrimidine D, which is treated with an arylamine C in asimilar fashion as above to provide the compound of Formula (II),wherein X₄ is not hydrogen. In exceptional cases, BOC deprotection isnot fully facilitated in the displacement reaction and the initialreaction product is further exposed to TFA or HCl to afford the desiredproduct.

Compounds of Formula (II), wherein W is C—F, can be prepared accordingto the synthetic sequence shown in Scheme 3 and further detailed in theExamples section following. 5-Fluorouracil (2) is converted to5-fluoro-2,4-dichloropyrimidine (3) by treatment with POCl₃. Theremaining steps in the synthesis of compounds of Formula (II), wherein Wis C—F, are parallel to those described above in Scheme 1 and/or Scheme2. Compounds of formula (III), wherein W is C—F, can be prepared byusing 5-fluoro-2,4-dichloropyrimidine (3) with appropriate adaptation ofScheme 10 following, such adaptation being within the purview of thoseskilled in the art.

Compounds of Formula (II), wherein W is N, can be prepared according toS the synthetic sequence shown in Scheme 4 and further detailed in theExamples section following. 2,4-Dichloro-1,3,5-triazine (4) is treatedwith an arylamine C in a suitable solvent (e.g., CH₃CN) to afford the achlorotriazine E. Compound E is further treated with arylamine A (X₄ isH or alkyl) to provide the compound of Formula (II). Compounds offormula (III), wherein W is N. can be prepared by using2,4-Dichloro-1,3,5-triazine (4) with appropriate adaptation of Scheme 10following, such adaptation being within the purview of those skilled inthe art.

The aniline moieties of Formula (I), depicted as structure C in Schemes1, 2 and 4 above, are available through multi-step organic synthesisfamiliar to one who is skilled in the art. The following schemesillustrate the methods that can be used to derive the anilines ofstructure C, which are incorporated into compounds of Formula (I) of thepresent invention.

As shown in Scheme 5, the appropriately substituted meta- or para-NO₂benzylamine can be condensed with an alkyl- or arylsulfonyl chlorideunder suitable conditions (e.g., triethylamine, CH₂Cl₂) to provide asulfonamide F. The NO₂ moiety of F can be reduced using SnCl₂/conc. HClor by hydrogenation (e.g., 10% Pd/C in methanol) to provide the desiredaniline. Other embodiments of the present invention can be derived fromanilines that are prepared as shown in Scheme 6. A nitro-substitutedbenzyl chloride G is converted to a sodium benzylsulfonate salt H byreaction at elevated temperature with Na₂SO₃ in a H₂O/dioxane mixture.Treatment of H with SOCl₂ (cat. DMF/CH₂Cl₂) provides the correspondingsulfonylchloride I, which can be treated with an amine to provide asulfonamide J. Reduction of the nitro group in J can be accomplished insimilar fashion as described above in Scheme 5.

Scheme 7 depicts the synthesis of other anilines of structure C that areuseful in the preparation of compounds of Formula (I). An appropriatethiolate anion undergoes a displacement reaction with anitro-substituted benzyl chloride G to provide a benzylic sulfide K.Oxidation of the sulfide, for example with mCPBA, provides thecorresponding sulfone, which is then reduced by standard methods to thedesired aniline C.

Scheme 8 depicts the synthesis of other anilines of structure C that areuseful in the preparation of compounds of Formula (I). The2-methoxyacetanilide undergoes chlorosulfonylation under standardconditions to provide the expected arylsulfonyl chloride L. Amination ofL with an amine affords a sulfonamide, which is hydrolyzed underappropriate conditions to provide the desired aniline C for use in thesynthesis of compounds of Formula (I).

Scheme 9 depicts the synthesis of other anilines of structure C that areuseful in the preparation of compounds of Formula (I). The para-methoxysulfenimide M can be prepared as described in the prior art.Mitsunobu-type substitution with an alcohol provides the phenyl sulfideN. (In certain cases, one who is skilled in the art will recognize thatthe same phenylsulfide N can be derived by alkylation of thepara-methoxy thiophenoxide anion with an alkyl halide.) Oxidation ofsulfide N affords a sulfone O, which undergoes nitration to provide themethoxynitrosulfone P. Methoxynitrosulfone P is reduced as alreadydescribed by the earlier scheme to the aniline C.

Scheme 10 depicts the synthesis of compounds of Formula (III). Asubstituted 6-nitroindazole Q undergoes alkylation by an appropriatealkylating agent (e.g., trimethyloxonium tetraflouroborate,triethyloxonium tetrafluoroborate, benzyl halide) to provide theN2-alkylated nitroindazole R. Reduction of the nitro group usingstandard conditions (e.g., SnCl₂, aqueous acid or 10% Pd/C, methanol,ammonium formate) followed by condensation with 2,4-dichloropyrimidineprovides the chloropyrimidine S. Alkylation of the bisaryl aminenitrogen under appropriate alkylation conditions (e.g., MeI, Cs₂CO₃,DMF) affords intermediate T, which undergoes subsequent condensationwith an appropriately substituted aniline to provide the compound ofFormula (III).

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification: g (grams); mg(milligrams); L (liters); mL (milliliters); μL (microliters); psi(pounds per square inch); M (molar); mM (millimolar); i.v.(intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol(millimoles); RT (room temperature); min (minutes); h (hours); mp(melting point); TLC (thin layer chromatography); T_(r) (retentiontime); RP (reverse phase); MeOH (methanol); I-PrOH (isopropanol); TEA(triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroaceticanhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); EtOAc(ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE(dichloroethane); DMF (N,N-dimethylformamide); DMPU(N,N′-dimethylpropyleneurea); (CDI (1,1-carbonyldiimidazole); IBCF(isobutyl chloroformate); HOAc (acetic acid); HOSu(N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); mCPBA(meta-chloroperbenzoic acid; EDC (ethylcarbodiimide hydrochloride); BOC(tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC(dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl); Ac (acetyl); atm(atmosphere); TMSE (2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS(triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP(4-dimethylaminopyridine); Me (methyl); OMe (methoxy); Et (ethyl); HPLC(high pressure liquid chromatography); tBu (tert-butyl). BOP(bis(2-oxo-3-oxazolidinyl)phosphinic chloride); TBAF(tetra-n-butylammonium fluoride); Et (ethyl);

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsconducted under an inert atmosphere at room temperature unless otherwisenoted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, or a General Electric QE-300. Chemicalshifts are expressed in parts per million (ppm, δ units). Couplingconstants are in units of hertz (Hz). Splitting patterns describeapparent multiplicities and are designated as s (singlet), d (doublet),t (triplet), q (quartet), m (multiplet), br (broad).

Low-resolution mass spectra (MS) were recorded on a JOEL JMS-AX₅₀₅HA,JOEL SX-102, or a SCIEX-APIiii spectrometer; high resolution MS wereobtained using a JOEL SX-102A spectrometer. All mass spectra were takenunder electrospray ionization (ESI), chemical ionization (CI), electronimpact (EI) or by fast atom bombardment (FAB) methods. Infrared (IR)spectra were obtained on a Nicolet 510 FT-IR spectrometer using a 1-mmNaCl cell. All reactions were monitored by thin-layer chromatography on0.25 mm E. Merck silica gel plates (60F-254), visualized with UV light,5% ethanolic phosphomolybdic acid or p-anisaldehyde solution. Flashcolumn chromatography was performed on silica gel (230-400 mesh, Merck).Optical rotations were obtained using a Perkin Elmer Model 241Polarimeter. Melting points were determined using a Mel-Temp IIapparatus and are uncorrected. The following examples describe thesyntheses of intermediates particularly useful in the synthesis ofcompounds of Formula (I),(II), (III), and (IV):

Intermediate Example 1 Preparation of 3-methyl-1H-indazol-6-amine

To a solution of 10 g (.06 mol) of 2-ethyl-5-nitroaniline (prepared bynitration of 2-ethylaniline: Bergman and Sand, Tetrahedron 1990, 46,6085-6112) in 300 ml of glacial acetic acid, at room temperature, wasadded a solution of 8.98 ml (.06 mol) of tert-butyl nitrite in 40 ml ofacetic acid dropwise over 15 min. After the addition was complete thesolution was allowed to stir for 30 min. The acetic acid was removed invacuo to afford an orange solid. The solid was dissolved inapproximately 120 ml of ethyl acetate and washed with 3×100 ml sat.aqueous NaHCO₃. The organic layer was dried over MgSO₄ and the solventwas removed in vacuo to afford 3-methyl-6-nitroindazole as a yellowsolid (10.4 g, 98%).

To a stirred solution of 10 g (.06 mol) of 3-methyl-6-nitroindazole in100 ml of 2-methoxyethyl ether, at 0° C., was added a solution of 45 g(.24 mol) of tin(II) chloride in 86 ml of concentrated HCl dropwise over15 min, in order to keep the reaction temperature below 100° C. Afterthe addition was complete, the ice bath was removed and the solution wasallowed to stir for an additional 20 min. Approximately 70 ml of diethylether was added to reaction, resulting in precipitate formation. Theresulting precipitate was isolated by filtration and washed with diethylether, and afforded a yellow solid (10 g, 92%), the HCl salt of3-methyl-1H-indazol-6-amine.

Intermediate Example 2 Preparation of N, 3-dimethyl-1H-indazol-6-amine

To a 100-mL flask containing 1.88 g (34.8 mmol) sodium methoxide and 60mL of dry methanol was added 1.27 g (6.96 mmol) of3-methyl-1H-indazol-6-amine hydrochloride. After stirring the mixture atroom temperature for 15 minutes, 0.38 g (12.6 mmol) of paraformaldehydewas added and the flask placed into a 60° C. oil bath for 10 minutes.The flask was then removed from the oil bath and allowed to stir at roomtemperature for 4.5 hours. To the reaction mixture was added 0.26 g(6.96 mmol) of sodium borohydride and the mixture heated to reflux for 2hours then allowed to cool to room temperature and stir overnight. Tothe reaction mixture was added 1M sodium hydroxide (13 mL). After 10minutes the reaction mixture was concentrated in vacuo to an aqueoussuspension. The suspension was diluted with 40 mL of water and pHadjusted to pH 8 with aq. hydrochloric acid. The aqueous suspension wasextracted three times with ethyl acetate, and the organic extractscombined and washed with brine, dried with sodium sulfate, and filtered.To the filtrate was added 5 g of silica gel and the resultant suspensionconcentrated to dryness in vacua. The solid was loaded on top of acolumn of 90 g of silica gel and eluted with chloroform/ethylacetate/methanol (9:0.5:0.5). The proper fractions were combined andconcentrated to give 0.43 g (39%) of N, 3-dimethyl-1H-indazol-6-amine asa white solid. HNMR: δ 11.88 (s, 1H), 7.29 (d, 1H), 6.44 (d, 1H), 6.20(s, 1H), 5.80 (brs, 1H), 2.67 (s, 3H) 2.32 (s, 3H); MS (ES+, m/z) 162(M+H).

Intermediate Example 3 Preparation of 2, 4-Dichloro-5-fluoropyrimidine

To 5-fluorouracil (5.0 g, 0.04 mol) was added phosphorus oxychloride (25mL, 0.27 mol) and N,N,-diethylaniline (6 mL, 0.06 mol) while stirring atroom temperature. After being heated under reflux for 100 min, themixture was concentrated under reduced pressure. The residue was pouredinto ice water (100 mL) and extracted with ether. The organic layer wasdried with sodium sulfate and evaporated at 0° C. under reduced pressureto give 5.35 g of the desired product (⁸ ⁵%). Mp 37-38° C. HNMR: δ 8.95(s, 1H).

Intermediate Example 4 Preparation ofN-(2-chloro-5-fluoro-4-pyrimidinyl)-N-(3-methyl-1H-indazol-6-yl)amine

To a stirred solution of 3-methyl-6-aminoindazole (2.71 g, 0.015 mol)and NaHCO₃ (1.26 g, 0.045 mol) in THF (15 mL) and EtOH (60 mL) was added5-fluoro-2,4-dichloropyrimidine (3.2 g, 0.019 mol) at room temperature.After the reaction was stirred overnight, the brown suspension wasfiltered and washed thoroughly with EtOH. The filtrate was concentratedunder reduced pressure, and the resulting solid was washed with ether toremove excess pyrimidine to yield 3.7 g of the desired product (89%).HNMR: δ 12.57 (s, 1H), 10.01 (s, 1H), 8.28 (d, 1H), 7.93 (s, 1H), 7.60(d, 1H), 7.27 (dd, 1H) 3.11 (s, 3H).

Intermediate Example 5 Preparation ofN-(2-chloro-5-4-pyrimidinyl)-N-(3-methyl-1H-indazol-6-yl)amine

To a stirred solution of 3-methyl-6-aminoindazole (2.71 g, 0.015 mol)and NaHCO₃ (1.26 g, 0.045 mol) in THF (15 mL) and ethanol (60 mL) wasadded 2,4-dichloropyrimidine (6.66 g, 0.045 mol) at room temperature.After the reaction was stirred for four hours, the suspension wasfiltered and washed thoroughly with ethanol. The filtrate wasconcentrated under reduced pressure, and the resulting solid was washedwith ether to remove excess pyrimidine to yield 3.5 g (89% yield) ofN-(2-chloro-4-pyrimidinyl)-N-(3-methyl-1H-indazol-6-yl)amine.

Intermediate Example 6 Preparation of tert-butyl6-[(2-chloro-5-fluoro-4-pyrimidinyl)amino]-3-methyl-1H-indazole-1-carboxylate

To a stirred suspension of the product of intermediate example 4 (3.0 g,0.011 mol), triethylamine (1.5 mL, 0.011 mol), 4-dimethylaminopyridine(0.13 g, 0.11 mmol), and acetonitrile (14 mL) was added DMF (50 mL) atroom temperature. Once the mixture was in solution, di-tet-butyldicarbonate (2.36 g, 0.011 mol) was added portion wise over threeminutes. After being stirred for 1 hour, the solution was diluted withwater and extracted with ether (3×40 mL). The combined extracts weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by silica gel columnchromatography (9:1, CH₂Cl₂:EtOAc), giving 3.3 g rams of the desiredproduct (85%).

Intermediate Example 7 Preparation of tert-butyl6-[(2-chloro-4-pyrimidinyl)amino]-3-methyl-1H-indazole-1-carboxylate

To a stirred suspension ofN-(2-chloro-4-pyrimidinyl)-N-(3-methyl-1H-indazol-6-yl)amine (2.8 g,0.011 mol), triethylamine (1.5 mL, 0.011 mol), 4-dimethylaminopyridine(0.13 g, 0.11 mmol), and acetonitrile (14 mL) was added DMF (50 mL) atroom temperature. Once the mixture is in solution, di-tert-butyldicarbonate (2.36 g, 0.011 mol) was added portion wise over threeminutes After being stirred for 1 hour, the solution was diluted withwater and extracted with ether (3×40 mL). The combined extracts weredried over sodium sulfate, filtered, and concentrated under reducedpressure. The resulting residue was purified by column chromatography(silica gel, 9:1 CH₂Cl₂— EtoAc), giving 3.3 grams (85% yield) oftert-butyl6-[(2-chloro-4-pyrimidinyl)amino]-3-methyl-1H-indazole-1-carboxylate.

Intermediate Example 8 Preparation of tert-butyl6-[(2-chloro-5-fluoro-4-pyrimidinyl)(methyl)amino]-3-methyl-1H-indazole-1-carboxylate

To a stirred solution of the product of Intermediate Example 6 (3.3 g,8.8 mmol) in 44 mL of DMF was added NaH (0.23 g, 9.6 mmol) portion wiseover 3 min at room temperature. After being stirred for 15 min,iodomethane (1.37 g, 9.6 mmol) was added dropwise. After being stirredfor 30 min, the reaction was quenched with water and extracted withether (3×30 mL). The combined extracts were dried over sodium sulfate,filtered, and concentrated under reduced pressure to yield a yellowsolid. The resulting solid was purified by silica gel columnchromatography (CH₂Cl2), giving 3.26 g of the desired product (95%).

HNMR: δ 8.18 (d, 1H), 7.90 (s, 1H), 7.82 (d, 1H), 7.35 (d, 1H), 3.45 (s,3H), 2.48 (s, 3H) 1.54 (s, 9H). MS (ES+, m/z) 292 (M+H).

Intermediate Example 9 Preparation of tert-butyl6-[(2-chloro-4-pyrimidinyl)(methyl)amino]-3-methyl-1H-indazole-1-carboxylate

This intermediate wherein W═H was prepared in similar fashion toIntermediate Example 8 described above.

Intermediate Example 10 Preparation of4-Chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine

To a dry flask containing a magnetic stir bar and a nitrogen atmospherewas added 0.247 g (1.33 mmol) of 3-[(methylsulfonyl)methyl]aniline, 2 mLdry acetonitrile and 0.23 mL (1.3 mmol) of diisopropylethyl amine andresultant mixture cooled in an ice bath. To the cold solution was addeda solution of 0.2 g (1.33 mmol) of 2,4-dichloro-1,3,5-triazine in 2.4 mLof dry acetonitrile over 1 min. The reaction mixture was stirred for ca.16 hrs and 1 gram of silica gel was added. The mixture was concentratedin vacuo to dryness and applied to the top of column of silica gel andeluted with a 15-50% ethyl acetate/dichloromethane gradient. The properfractions were combined and concentrated in vacuo to give 0.28 g (70%)of 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amineas a white solid. HNMR: δ 10.83 (s, 1H), 8.64 (s, 1H), 7.63 (m, 2H), 7.4(t, 1H), 7.25 (d, 1H), 4.48 (s, 2H), 2.94 (s, 3H); MS (ES+, m/z) 299,301 (M+H).

Intermediate Example 11 Preparation of 2,3-dimethyl-2H-indazol-6-amine

To a stirred solution of 18.5 g (0.11 mol) of3-methyl-6-nitro-1H-indazole in 350 ml acetone, at room temperature, wasadded 20 g (0.14 mol) of trimethyloxonium tetraflouroborate. After thesolution was allowed to stir under argon for 3 hours, the solvent wasremoved under reduced pressure. To the resulting solid was addedsaturated aqueous NaHCO₃ (600 ml) and a 4:1 mixture ofchloroform-isopropanol (200 ml), and the mixture was agitated and thelayers were separated. The aqueous phase was washed with additionalchloroform: isopropanol (4×200 ml) and the combined organic phase wasdried (Na₂SO₄). Filtration and removal of solvent gave a tan solid. Thesolid was washed with ether (200 ml) to afford2,3-dimethyl-6-nitro-2H-indazole as a yellow solid (15.85 g, 73%). ¹HNMR (300 MHz, d₆DMSO) δ 8.51 (s, 1H), 7.94 (d, J=9.1 Hz, 1H), 7.73 (d,J=8.9 Hz, 1H), 4.14 (s, 3H), 2.67 (s, 3H). MS (ES+, m/z) 192 (M+H).

To a stirred solution of 2,3-dimethyl-6-nitro-2H-indazole (1.13 g ) in2-methoxyethyl ether (12 ml), at 0° C., was added a solution of 4.48 gof tin(II) chloride in 8.9 ml of concentrated HCl dropwise over 5 min.After the addition was complete, the ice bath was removed and thesolution was allowed to stir for an additional 30 min. Approximately 40ml of diethyl ether was added to reaction, resulting in precipitateformation. The resulting precipitate was isolated by filtration andwashed with diethyl ether, and afforded a yellow solid (1.1 g, 95%), theHCl salt 2,3-dimethyl-2H-indazol-6-amine. ¹H NMR (300 MHz, d₆DMSO) δ7.77 (d, J=8.9 Hz, 1H), 7.18 (s, 1H), 7.88 (m, 1H), 4.04 (s, 3H), 2.61(s, 3H). MS (ES+, m/z) 162 (M+H).

Intermediate Example 12 Preparation ofN-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine

To a stirred solution of Intermediate Example 11 (2.97 g, 0.015 mol) andNaHCO₃ (5.05 g, 0.06 mol) in THF (15 mL) and ethanol (60 mL) was added2,4-dichloropyrimidine (6.70 g, 0.045 mol) at room temperature. Afterthe reaction was stirred for four hours at 85° C., the suspension wascooled to rt., filtered and washed thoroughly with ethyl acetate. Thefiltrate was concentrated under reduced pressure, and the resultingsolid was triturated with ethyl acetate to yield 3.84 g (89% yield) ofN-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine. ¹H NMR (400MHz, d₆DMSO) δ 7.28 (d, J=9.0 Hz, 1H), 6.42 (d, J=8.8 Hz, 1H), 6.37 (s,1H), 5.18 (br s, 1H), 3.84 (s, 3H), 2.43 (s, 3H). MS (ES+, m/z) 274(M+H).

Intermediate Example 13 Preparation ofN-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine

To a stirred solution of the Intermediate 12 (7.37 g ) in DMF (50 ml)was added Cs₂CO₃ (7.44 g, 2 eqv.) and MeI (1.84 ml, 1.1 eqv.) at roomtemperature. Mixture was stirred at rt for overnight. The reactionmixture was poured into ice-water bath, and the precipitate wascollected via filtration and washed with water. The precipitate wasair-dried to affordN-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine as anoff-white solid (6.43 g, 83%). ¹H NMR (400 MHz, d₆DMSO) δ 7.94 (d, J=6.0Hz, 1H), 7.80 (d, J=7.0 Hz, 1H), 7.50 (d, J=1.0 Hz, 1H), 6.88 (m, 1H),6.24 (d, J=6.2 Hz, 1H), 4.06 (s, 3H), 3.42 (s, 3H), 2.62 (s, 3H). MS(ES+, m/z) 288 (M+H).

Intermediate Example 14 Preparation of2-Chloro-5-({4-[(2,3-dimethyl-2--indazol-6-yl)amino]-1,3,5-triazine

Intermediate Example 11 (free base) (0.080 g, 0.5 mmol), and2,4-dichloro-1,3,5-triazine (Harris, R. L. N.; Amide-acid chlorideadducts in organic synthesis. Part 12. The synthesis of triazines formN-cyanocarbamimidates. SYNTHESIS (1981), 11, 907-8) (0.075 g, 0.5 mmol),were combined in acetonitrile. DIEA was added and the solution wasstirred at RT for 18 h. The resulting precipitate was filtered off andwashed with acetonitrile to give analytically pure product as a lightyellow solid (0.10 g, 0.36 mmol). ¹H NMR (300 MHz, d₆DMSO) δ 10.73 (s,1H), 8.63 (d, J=15.3 Hz, 1H), 7.94 (d, J=7.7 Hz, 1H), 7.62 (d, J=8.9 Hz,1H), 7.13 (d, J=7.9 Hz, 1H), 4.01 (s, 3H), 2.57 (s, 3H). MS (ES+, m/z)275 (M+H).

Intermediate Example 15 Preparation of2-Chloro-5-({4-[(2,3-dimethyl-24indazol-6-yl)(methyl)amino]-1,3,5-triazine

Intermediate Example 14 (0.05 g, 0.18 mmol) was combined with cesiumcarbonate (0.088 g, 0.27 mmol), and DMF (1 mL). Methyl iodide (0.033 mL,0.54 mmol) was added and the solution was stirred at RT for 18 h. Waterwas added and the solution was washed with diethyl ether. The organiclayer was dried with magnesium sulfate, filtered, and concentrated, togive a light yellow glass (0.035 g, 0.12 mmol) which was >90 pure byHPLC. This material was used directly in the next step. ¹H NMR (300 MHz,d₆DMSO) δ 8.6 (br s, 1H), 7.70 (d, J=8.2 Hz, 1H), 7.48 (s, 1H), 6.90 (d,J=8.0 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H), 2.60 (s, 3H). MS (ES+, m/z)289 (M+H).

Intermediate Example 16 Preparation ofN¹-methyl-4-nitrobenzene-1,2-diamine

In a 350 mL pressure flask, 2-fluoro-5-nitroaniline (10 g, 0.064 mol),methylamine as a 2M solution in THF (65 mL, 0.13 mol) and potassiumcarbonate (18 g, 0.13 mol) in 1-Methyl-2-pyrrolidinone (80 mL) werecombined. The flask was sealed and heated to 120 degrees C. overnight.The reaction was monitored by TLC. When reaction was judged to becomplete based upon consumption of 2-fluoro-5-nitroaniline, it wascooled to room temperature and poured into 2-3 times the total reactionvolume of water. When a precipitate was formed, it was filtered anddried. The product was carried on without purification. 1H NMR (300 MHz,d₆DMSO) δ 7.54 (dd, J=8.79, 2.64 Hz, 1H), 7.39 (d, J≦2.64 Hz, 1H), 6.41(d, J=8.79 Hz, 1H), 6.11 (d, J=4.39 Hz, 1H), 5.07 (s, 2H), 2.83 (d, 1H),4.83 Hz, 3H).

Intermediate Example 17 Preparation of1,2-dimethyl-5-nitro-1H-benzimidazole

Intermediate Example 16 (7 g, 0.042 mol) and trimethoxy orthoacetate(5.86 mL, 0.046 mol) were combined in 4N HCl (70 mL). The reaction washeated to reflux and followed by TLC. When reaction was judged to becomplete based upon consumption of diamine, it was slowly poured into 6NNaOH (65 mL) and ice and allowed to stir until the pH was greater than7.0. The product was extracted with EtOAc, dried over sodium sulfate,filtered and concentrated. The resulting material was carried on withoutpurification. 1H NMR (300 MHz, d₆DMSO) δ 8.39 (d, J=2.20 Hz, 1H), 8.12(dd, J=8.94, 2.20 Hz, 1H), 7.71 (d, J=8.94 Hz, 1H), 2.58 (s, 3H), 3.80(s, 3H).

Intermediate Example 18 Preparation of Preparation of2-benzyl-1-methyl-5-nitro-1H-benzimidazole

Intermediate Example 16 (2.3 g, 0.014 mol) and phenylacetic acid (2.8 g,0.021 mol) were combined in 4N HCl (30 mL). The reaction was heated toreflux and followed by TLC. When reaction was judged to be completebased upon consumption of diamine, it was slowly poured into 6N NaOH (27mL) and ice and allowed to stir until the pH was greater than 7.0. Theproduct was extracted with EtOAc, dried over sodium sulfate, filteredand concentrated. The resulting material was generally carried onwithout purification. 1H NMR (300 MHz, d₆DMSO) δ8.46 (d, J=2.20 Hz, 1H),8.14 (dd, J=8.94, 2.20 Hz, 1H,) 7.72 (d, J=8.94 Hz, 1H) 7.30 (m, 5H),4.37 (s, 2H), 3.79 (s, 3H).

Intermediate Example 19 Preparation of1,2-dimethyl-1H-benzimidazol-5-amine

Intermediate Example 17 (7 g, 0.037 mol) and 10% Pd/C (0.7 g ) in aconcentrated methanol solution were shaken under approximately 40 psi ofH₂ in appropriate pressure vessel using a Parr Hydrogenator. When thereaction was judged to be complete based upon the consumption of thenitrobenzimidazole, it was diluted with EtOAc and filtered throughCelite and silica gel, which was washed with a mixture of EtOAc and MeOHand concentrated. The product was carried on without purification. 1HNMR (300 MHz, d₆DMSO) δ 7.11 (d, J=8.38 Hz, 1H), 6.69 (d, J1.51 Hz, 1H),6.53 (dd, J=8.38, 1.51 Hz, 1H), 4.65 (s, 2H), 3.62 (s, 3H), 2.43 (s,3H).

Intermediate Example 20 Preparation ofN-(2-chloropyrimidin-4-yl)-1,2-dimethyl-1H-benzimidazol-5-amine

Intermediate Example 19 (4.5 g, 0.028 mol) and sodium bicarbonate (4.69g, 0.056 mol) were combined in a 2:1 mixture of EtOH:THF (180 mL).2,4-dichloropyrimidine (8.32 g, 0.056 mol) was added and the reactionwas heat to 80 degrees C. The reaction was monitored by TLC. Whenreaction was judged to be complete based upon the consumption ofaminobenzimidazole, the reaction was filtered while hot and the filtratewas concentrated. The resulting solid was washed with ether and EtOAc toremove excess 2,4-dichloropyrimidine and the resulting solid was carriedon without purification. 1H NMR (300 MHz, d₆DMSO) δ 9.97 (s, 1H) 8.11(d, J=5.91 Hz, 1H) 7.80 (s, 1H) 7.48 (d, J=8.52 Hz, 1H) 7.27 (d, J=7.83Hz, 1H) 6.68 (d, J=5.91 Hz, 1H) 3.74 (s, 3H) 2.54 (s, 3H).

Intermediate Example 21 Preparation ofN-(2-chloropyrimidin-4-yl)-N,1,2-trimethyl-1H-benzimidazol-5-amine

Intermediate Example 20 (6.5 g, 0.024 mol) was dissolved in DMF (70 mL).Sodium hydride (1.06 g of 60% dispersion in mineral oil, 0.026 mol) wasslowly added in portions and the reaction was allowed to stir for 20minutes under nitrogen. Methyl iodide (1.65 mL, 0.026 mol) was added andthe reaction stirred for an additional 30 minutes. The reaction wasmonitored by TLC. When the reaction was judged to be complete based uponconsumption of the anilinopyrimidine, water was slowly added to quenchexcess sodium hydride and product was extracted with EtOAc. The combinedorganic layers were washed with water to remove DMF, dried over sodiumsulfate, filtered and concentrated. The reaction was chromatographed onsilica gel using CH₂Cl₂ and MeOH as eluent to purify. 1H NMR (300 MHz,d₆DMSO) δ 7.89 (d, J=6.15 Hz, 1H) 7.59 (d, J=8.50 Hz, 1H) 7.50 (d,J=1.76 Hz, 1H) 7.13 (dd, J=8.50, 1.90 Hz, 1H) 6.10 (d, J=5.27 Hz, 1H)3.75 (s, 3H) 3.41 (s, 3H) 2.53 (s, 3H).

Example 1 recites the general procedure for the synthesis of compoundsof formula (I) and (II) wherein W═C—F:

Example 1N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-5-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

To a stirred suspension of the product of Intermediate Example 8 (2.0 g,5.1 mmol) and 3-amino-4-methoxyphenyl ethyl sulfone (1.2 g, 5.6 mmol),in 10 mL of isopropanol, was added a drop of concentrated HCl at 80° C.After being stirred for 15 hr, the suspension was concentrated underreduced pressure. The resulting residue was diluted with 5 mL CH₂Cl₂ and5 mL trifluoroacetic acid and stirred for 30 min at room temperature,then was diluted with CH₂Cl₂ (3×40 mL), and washed with saturatedNaHCO₃. The extracts were dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bysilica gel column chromatography (4:1, CH₂Cl₂:EtOAc), giving 1.0 g (42%)ofN²-[5-(ethylsulfonyl)-2-methoxyphenyl]-5-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamineas a white solid. HNMR (400 MHz, d₆₋DMSO): δ 12.60 (bs,1H), 8.91 (bs,1H), 7.96 (d,1H, J=5.5), 7.92 (s, 1H), 7.64 (d, 1H, J=8.6), 7.42 (d, 1H,J=8.4), 7.31 (s, 1H), 7.22 (d,1H, J=8.6), 6.99 (d, 1H, J=8.4), 3.94 (s,3H), 3.48 (s, 3H), 3.14 (q, 2H, J=7.3), 2.44 (s, 3H),1.04 (t, 3H,J=7.4).

The compounds of Examples 2-15 were prepared according to the generalprocedure set forth in Example 1.

Example 23-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-4-methoxy-N-methylbenzenesulfonamide

HNMR (400 MHz, d₆₋DMSO): δ 12.60 (s,1H), 8.89 (s, 1H), 7.95 (d,1H), 7.91(s, 1H), 7.64 (d, 1H), 7.31 (3H, m), 7.00 (d, 1H), 4.04 (m, 1H), 3.94(s, 3H), 3.48 (s, 3H), 3.11 (s, 3H), 1.10 (d, 6H); MS (ES+, m/z)=442(M+H).

Example 35-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine

HNMR (400 MHz, d₆₋DMSO): δ 12.65 (br s, 1H), 10.05 (s, 1H), 8.06 (d,1H), 7.70 (d, 1H), 7.64 (s, 1H), 7.54 (d, 1H), 7.40 (m, 1H), 7.22 (m,1H), 7.02 (m, 2H), 4.52 (s, 2H), 4.36 (s, 3H), 3.43 (s, 3H), 2.87 (s,3H); MS (ES+, m/z)=441 (M+H).

Example 43-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-N-isopropyl-4-methoxybenzenesulfonamide

HNMR (400 MHz, d₆₋DMSO): δ 12.59 (s, 1H), 8.83 (s, 1H), 7.93 (d, 1H),7.85 (s, 1H), 7.65 (d, 1H), 7.43 (s, 1H), 7.36 (d, 1H), 7.30 (s, 1H),7.28 (d, 1H), 7.16 (d, 1H), 6.99 (d, 1H), 3.91 (s, 3H), 3.47 (s, 3H),3.16 (m, 1H), 0.89 (d, 6H); MS (ES+, m/z)=470 (M+H).

Example 55-fluoro-N²-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR (400 MHz, d₆₋DMSO): δ 12.60 (s, 1H), 8.89 (s, 1H), 7.98 (d, 1H),7.91 (s, 1H), 7.64 (d, 1H), 7.31 (m, 3H), 7.00 (d, 1H), 4.04 (m, 1H),3.94 (s, 3H), 3.48 (s, 1H), 3.11 (s, 3H), 1.10 (d, 6H); MS (ES+,m/z)=485 (M+H).

Example 6[5-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-2-methylphenyl]methanesulfonamide

HNMR (400 MHz, d₆₋DMSO): δ 12.66 (br s, 1H), 9.56 (s, 1H), 8.98 (s, 1H),7.95 (d, 1H), 7.66 (d, 1H), 7.57 (s, 1H), 7.41 (d, 1H), 7.33 (s, 1H),7.03 (d, 1H), 7.00 (d, 1H), 3.48 (s, 3H), 2.93 (s, 3H), 2.44 (s, 3H),2.18 (s, 3H); MS (ES+, m/z)=456 (M+H).

Example 75-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-[4-(methylsulfonyl)phenyl]-2,4-pyrimidinediamine

HNMR (400 MHz, d₆₋DMSO): δ 12.68 (s, 1H), 9.80 (s, 1H), 8.01 (d, 1H),7.76 (d, 1H), 7.66 (d, 1H), 7.58 (d, 1H), 7.36 (s, 1H), 7.01 (d, 1H),3.48 (s, 3H), 3.05 (s, 3H), 2.38 (s, 3H); MS (ES+, m/z)=427 (M+H).

Example 8N⁴-(3-ethyl-1H-indazol-6-yl)-5-fluoro-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine

HNMR (400 MHz, d₆₋DMSO): δ 12.57 (br s, 1H), 9.35 (s, 1H), 7.92 (d, 1H,J=5.7), 7.75 (br s, 1H), 7.67 (d, 1H, J=8.6), 7.60 (d, 1H, J=8.5), 7.28(s, 1H), 7.14 (dd, 1H, J=7.8, 7.9), 6.97 (d, 1H, J=8.4), 6.87 (d, 1H,J=7.5), 4.31 (s, 2H), 3.47 (s, 3H), 2.88 (m, 2H), 2.85 (s, 3H), 1.26 (t,3H, J=7.6); MS (AP+, m/z)=455 (M+H).

Example 94-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

HNMR (400 MHz, d₆₋DMSO): δ 12.65 (br s, 1H), 9.81 (s, 1H), 8.01 (d, 1H),7.75 (d, 1H), 7.67 (d, 1H), 7.59 (d, 2H), 7.33 (s, 1H), 7.10 (br s, 1H),7.00 (d, 1H), 3.80 (s, 1H), 3.49 (s, 3H), 2.40 (s, 3H); MS (ES+,m/z)=428 (M+H).

Example 10N⁴-ethyl-5-fluoro-N²-[2-methoxy-5-(methylsulfonyl)phenyl]-B⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR (400 MHz, d₆₋DMSO): δ 12.57 (s, 1H), 9.32 (s, 1H), 7.89 (s, 1H),7.72 (s, 1H), 7.64 (d, 1H), 7.59 (d, 1H), 7.25 (s, 1H), 6.95 (d, 1H),6.87 (d, 1H), 4.29 (s, 3H), 3.98 (q, 2H), 2.86(s, 3H), 2.43 (s, 3H),1.15 (t, 3H); MS (ES+, m/z)=471 (M+H).

Example 11[4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]-N-methylmethanesulfonamide

HNMR (400 MHz, d₆₋DMSO): δ 12.57 (s, 1H), 9.35 (s, 1H), 7.92 (d, 1H),7.66 (d, 1H), 7.64 (s, 1H), 7.63 (d, 1H), 7.28 (s, 1H), 7.16 (d, 1H),7.13 (d, 1H), 6.87 (d, 1H), 4.29 (s, 2H), 3.47 (s, 3H), 4.14 (s, 1H),2.80 (s, 3H), 2.48 (s, 3H); MS (ES+, m/z)=456 (M+H).

Example 125-fluoro-N²-{3-[(isopropylsulfonyl)methyl]phenyl}-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR (400 MHz, d₆₋DMSO): δ 12.70 (br s, 1H), 9.73 (s, 1H), 7.99 (d, 1H),7.72 (s, 1H), 7.67 (d, 1H), 7.56 (d, 1H), 7.35 (s, 1H), 7.18 (dd, 1H),7.01 (d, 1H), 6.95 (d, 1H), 4.32 (s, 2H), 3.50 (s, 3H), 3.13 (m, 1H),2.43 (s, 3H), 1.21 (d, 6H); MS (ES+, m/z)=469 (M+H).

Example 133-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-4-methoxybenzamide

HNMR (400 MHz, d₆₋DMSO): δ 12.62 (s, 1H), 8.80 (d, 1H), 7.95 (d, 1H),7.79 (s, 1H), 7.78 (brs, 1H), 7.68 (d, 1H), 7.53 (dd, 1H), 7.32 (s, 1H),7.11 (brs, 1H), 7.05 (d, 1H), 7.02 (d, 1H), 3.92 (s, 3H), 3.49 (s, 3H),2.47 (s, 3H); MS (ES+, m/z)=422 (M+H).

Example 144-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-3-methoxybenzenesulfonamide

HNMR (400 MHz, d₆₋DMSO): δ 12.30 (br s, 1H), 8.77 (s, 1H), 8.10 (d, 1H),7.73 (d, 1H), 7.54 (d, 1H), 7.44 (s, 1H), 7.24 (d, 1H), 7.22 (s, 1H),7.20 (brs, 2H), 7.08 (d, 1H), 3.96 (s, 3H), 3.55 (s, 3H), 2.47 (s, 3H);MS (ES+, m/z)=457 (M+H).

Examples 15 and 16 recite the general procedure for the synthesis ofcompounds of formula (I) and (II) wherein W═N:

Example 15N²-(3-methyl-1H-indazol-6-yl)-N⁴-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diaminetrifluoroacetate

To a flask containing a magnetic stir bar was added 0.03 g (0.20 mmol)of 3-methyl-1H-indazol-6-amine and 0.060 g (0.20 mmol) of4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and2 mL of isopropanol and the resultant mixture was heated at reflux forca. 16 hours. Upon cooling the reaction mixture a solid precipitated.The solid was filtered and washed with ethyl acetate (2×4 mL),acetonitrile (4 mL), and ethyl ether (4 mL) and dried under vacuum togiveN²-(3-methyl-1H-indazol-6-yl)-N⁴-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diaminehydrochloride as a solid. The solid was purified by C-18 RP-HPLC usingan acetonitrile/water gradient containing 0.5% trifluoroacetic acidbuffer. Concentrating the proper fractions gave 0.015 g (10%) ofN²-(3-methyl-1H-indazol-6-yl)-N⁴-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diaminetrifluoroacetate as a white solid. HNMR: δ12.4 (br s, 1H), 9.9 (br s,1H), 8.34 (s, 1H), 7.8 (br s, 1H), 7.67 (br s, 1H), 7.56 (d, 1H),7.29(m, 2H), 7.02 (d, 1H), 4.34 (br s, 2H), 2.83 (br s, 3H), 2.40 (s,3H). MS (ES+, m/z)=409 (M+H).

Example 16N²-methyl-N²-(3-methyl-1H-indazol-6-yl)-N⁴-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diaminehydrochloride

To a flask containing a magnetic stir bar was added 0.027 g (0.17 mmol)of N,3-dimethyl-1H-indazol-6-amine and 0.058 g (0.19 mmol) of4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and2 mL of isopropanol and the resultant mixture heated at reflux for ca.16 hours. Upon cooling the reaction mixture a solid precipitated. Thesolid was filtered and washed with ethyl acetate (2×4 mL), acetonitrile(4 mL), and ethyl ether (4 mL) and dried under vacuum to give 0.03 g(42%) of N²-methyl-N²-(3-methyl-1H-indazol-6-yl)-N⁴-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diamine hydrochloride as a light pinksolid. Some of the peaks in the NMR spectrum are broad at roomtemperature. Heating to 90° C. produces peaks that are well resolved.HNMR: δ12.5 (br s, 1H), 9.9 (br s, 1H), 8.24 (m, 1H) 7.72 (d, 1H) 7.5(m), 7.38 (s, 1H), 7.01 (d, 1H) 6.9 (br s, 1H) 3.47 (s, 3H), 2.75 (br s,3H), 2.47 (S, 3H). HNMR (at 90° C.): δ 9.62 (s, 1H), 8.29 (s, 1H), 7.76(d, 1H), 7.66 (s, 1H), 7.54 (d, 1H), 7.43 (s, 1H) 7.1 (m, 3H), 4.13 (s,2H), 3.56 (s, 3H), 2.93 (s, 3H), 2.55 (s, 3H); MS (ES+, m/z)=424 (M+H).

In most cases the hydrochloride salts are obtained in sufficient purity.When this is not the case, the amine hydrochloride salts are purifiedeither by Reverse Phase High Pressure Liquid Chromatography (RPHPLC), orby normal phase chromatography by loading the solids on 1 g ram ofsilica gel. The silica gel mixture is then loaded on top of a column ofsilica gel and eluted with a chloroform/ethyl acetate to methanol/ethylacetate gradient. As stated above, some of the peaks in the NMR spectrumare broad at room temperature. Heating to 90° C. produces peaks that arewell resolved.

The compounds of Examples 17-20 were prepared according to the generalprocedures set forth above in Examples 15 and 16.

Example 17N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-1,3,5-triazine-2,4-diaminehydrochloride

HNMR (d₆DMSO, 300 MHz): δ 8.89 (br s, 1H), 8.56 (br s, 1H), 8.26 (s,1H), 7.72 (d, 1H), 7.62 (d, 1H), 7.41 (s, 1H), 7.31 (d, 1 H), 7.04 (d,1H), 3.95 (s, 3H), 3.50 (s, 3H), 3.13 (br s, 2H), 1.08 (t, 3H). At 90degrees, peaks sharpen and peak at 3.13 resonates as a quartet. MS (AP+,m/z)=454 (M+1).

Example 18N-[2-methyl-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-1,3,5-triazin-2-yl}amino)phenyl]methanesulfonamide

HNMR (d₆DMSO, 300 MHz): δ 12.60 (br s, 1H), 9.6 (br s, 1H), 8.92 (br s,1H), 8.15 (br s, 1H) 7.67 (d, 1H), 7.52 (br S, 1H), 7.39 (br s, 1H),7.34 (s, 1H), 6.99 (d, 1H), 3.46 (s, 3H), 2.89 (s, 3H), 2.14 (s, 3H).HNMR (d₆DMSO @ 90° C., 300 MHz): δ 12.46 (br s, 1H), 9.39 (s, 1H), 8.73(s, 1H), 8.23 (s, 1H), 7.73 (d, 1H), 7.59 (s, 1 H), 7.47 (d, 1H), 7.40(s, 1H), 7.06 (d, 1H), 6.93 (d, 1H), 3.55 (s, 3H), 2.99, (s, 3 H), 2.24(s, 3H). MS (AP+, m/z)=439 (M+1).

Example 19N²-methyl-N²-(3-methyl-1H-indazol-6-yl)-N⁴-[3-(methylsulfonyl)phenyl]-1,3,5-triazine-2,4-diamine

HNMR (d₆DMSO @ 90° C., 300 MHz): δ 12.48 (br s, 1H), 9.82 (s, 1H), 8.36(s, 1H), 8.30 (s, 1H), 7.91 (d, 1H), 7.75 (d, 1H), 7.50 (d, 1H), 7.43(s, 1H), 7.33 (t, 1H), 7.07 (d, 1H), 3.57 (s, 3H), 2.54 (s, 3H). Note:at room temperature, the SO2CH3 group resonates at 3.05 as a broadsinglet, whereas at 90° C., the SO2CH3 group resonates under the H2Opeak. MS (ES+, m/z)=410 (M+1).

Example 20N-[4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-1,3,5-triazin-2-yl}amino)phenyl]acetamidehydrochloride

HNMR (d₆DMSO @ 90° C., 300 MHz): δ 9.58 (s, 1H), 9.54 (s, 1H), 8.27(s,1H), 7.75 (d, 1H), 7.50 (s, 1H), 7.45 (d, 2H), 7.33 (d, 2H), 7.08 (d,1H), 3.56 (s, 3H), 2.56 (s, 3H), 2.03 (s, 3H). MS (ES+, m/z)=389 (m+1).

Example 21 recites the general procedure for the synthesis of compoundsof formula (I) and (II) wherein W═C—H:

Example 213-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamidehydrochloride

To a solution of Intermediate Example 9 (200 mg, 0.535 mmol) and3-aminobenzenesulfonamide (92.1 mg, 0.535 mmol) in isopropanol (6 ml)was added 4 drops of conc. HCl. The mixture was heated to refluxovernight. The mixture was cooled to rt and diluted with ether (6 ml).Precipitate was collected via filtration and washed with ether.3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-benzenesulfonamidewas isolated as off-white solid (214 mg).

¹H NMR (300 MHz, d₆DMSO) δ 12.73 (br s, 1H), 9.54 (s, 1H), 8.55 (s, 1H),7.86 (d, J=6.0 Hz, 1H), 7.78-7.81 (m, 2H), 7.40 (s, 1H), 7.33-7.34 (m,2H), 7.25 (br s, 2H), 7.02 (d, J=8.4 Hz, 1H), 5.82 (d, J=6.0 Hz, 1H),3.51 (s, 3H), 2.50 (s, 3H). MS (ES+, m/z) 410 (M+H).

Unless otherwise indicated, the compounds of Examples 22-37 and 41-68were prepared according to the general procedures set forth above inExample 21. In most cases the hydrochloride salts of these examples werereadily obtained as described in the experimental above. In certaincases it was more convenient to isolate the final compound as its freebase by partitioning with an organic solvent (e.g., ethyl acetate) andan aqueous base (e.g. aqueous sodium bicarbonate). It will be readilyapparent to those skilled in the art that the syntheses of theseexamples will use either of Scheme 1 or Scheme 2 described above,depending on group X_(4,) the nature of which defines the alkylatingagent whose use is described in Scheme 2. The NMR data characterizingthese examples describe either the salt form or the free base form.

Example 22N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR: δ 12.74 (s, 1H), 9.10 (s, 1H), 7.85 (d, J=6.0 Hz, 1H), 7.81 (s,1H), 7.79 (d, J=8.2 Hz, 1H), 7.46 (d, J=8.6 Hz, 1H), 7.41 (s, 1H), 7.25(d, J=8.2 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 5.78 (d, J=6.0 Hz, 1H), 3.99(s, 3H), 3.51 (s, 3H), 3.18 (q, J=7.4 Hz, 2H), 2.50 (s, 3H), 1.09 (t,J=7.4 Hz, 3H); MS (ES+, m/z)=451, 452 (M+H).

Example 23N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine

HNMR: δ 12.70 (s, 1H), 9.24 (s, 1H), 7.85 (d, J=6.1 Hz, 1 H), 7.81 (s,1H), 7.78 (d, J=8.5 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.37 (s, 1H), 7.15(t, J=7.9 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.89 (d, J=7.5 Hz, 1H), 5.81(d, J=6.1 Hz, 1H), 4.27 (s, 1H), 3.49 (s, 3H), 2.86 (s, 3H), 2.51 (s,3H); MS (ES+, m/z)=423, 424 (M+H).

Example 24N-isopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

HNMR: δ 12.84 (s, 1H), 10.26 (s, 1H), 8.39 (s, 1H), 7.85 (d, J=6.5 Hz,1H), 7.83 (d, J=5.0 Hz, 1H), 7.72 (s, 1H), 7.57 (d, J=7.4 Hz, 1H), 7.48(s, 1H), 7.47 (s,1H), 7.05 (d, J=8.4 Hz, 1H), 5.90 (d, J=6.5 Hz, 1H),(s, 1H), 3.54 (s, 3H), 3.25 (septet, J=6.8 Hz, 1H), 2.51 (s, 3H), 0.95(d, J=6.8 Hz, 6H).

Example 25N-cyclopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

HNMR: δ 12.72 (s, 1H), 9.57 (s, 1H), 8.57 (s, 1H), 7.85 (d, J=6.1 Hz,1H), 7.80 (s, 1H), 7.78 (d, J=5.2 Hz, 1H), 7.39 (s, 1H), 7.37 (t, J=8.1Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 5.79 (d, J=6.1Hz, 1H), 3.51 (s, 3H), 2.51 (s, 3H), 2.18-2.10 (m, 1H), 0.51-0.30 (m,4H).

Example 26N⁴-ethyl-N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR: δ 12.70 (s, 1H), 9.00 (s, 1H), 7.78 (s, 1H), 7.76 (d, 1H), 7.74(d, 1H), 7.42 (d, 1H), 7.33 (s, 1H), 7.22 (d, 1H), 6.92 (d, 1H), 5.57(d, 1H), 4.05 (q, 2H), 3.95 (s, 3H), 3.43 (s, 3H), 3.12 (q, 2H), 1.14(t, 3H), 1.06 (t, 3H); MS (ES+, m/z)=485 (M+H).

Example 27N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]methanesulfonamide

HNMR: δ 12.66 (s, 1H), 9.24 (s, 1H), 9.16 (s, 1H), 7.78 (d, J=5.9 Hz,1H), 7.74 (d, J=8.3 Hz, 1H), 7.65 (s, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.33(s, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.67 (d, J=7.9Hz, 1H), 5.71 (d, J=5.9 Hz, 1H), 3.44 (s, 3H), 2.92 (s, 3H), 2.46 (s,3H); MS (ES+, m/z)=424, 426 (M+H).

Example 28N²-{3-[(isopropylsulfonyl)methyl]phenyl}-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR: δ 12.88 (s, 1H), 10.37 (s, 1H), 7.86 (d, J=6.5 Hz, 1H), 7.82 (d,J=8.6 Hz, 1H), 7.67 (s, 1H), 7.56 (d, J=7.9 Hz, 1H), 7.29 (s, 1H), 7.12(d, J=7.3 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 5.95 (d, J=6.5 Hz, 1H), 4.38(s, 2H), 3.55 (s, 3H), 3.16 (septet, J=6.8 Hz, 1H), 2.51 (s, 3H), 1.26(d, J=6.8 Hz, 6H); MS (ES+, m/z)=451, 452 (M+H).

Example 29N²-{4-[(isopropylsulfonyl)methyl]phenyl}-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR: δ 12.87 (s, 1H), 10.21 (s, 1H), 7.85 (d, J=6.2 Hz, 1H), 7.83 (d,J=8.5 Hz, 1H), 7.57 (d, J=8.1 Hz, 2H), 7.49 (s, 1H), 7.30 (d, J=8.5 Hz,1H), 7.05 (d, J=8.1 Hz, 2H), 5.98 (d, J=6.2 Hz, 1H), 4.39 (s, 2H), 3.54(s, 3H), 3.14 (septet, J=6.3 Hz, 1H), 2.51 (s, 3H), 1.26 (d, J=6.3 Hz,6H), MS (ES+, m/z)=451, 452 (M+H).

Example 30N²-[5-(isobutylsulfonyl)-2-methoxyphenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR (400 MHz, d₆-DMSO) δ 12.29 (s,1H), 9.57 (s,1H), 8.75 (dd,1H,J=2.14Hz and J=6.42 Hz), 8.05 (d, 1H, J=5.89, 1H), 7.87 (br s, 1H), 7.77(d,1H,J=2.85 Hz), 7.54 (d, 1H, J=8.74 Hz), 7.47 (dd, 1H, J=2.14 Hz andJ=8.56 Hz), 7.23 (d, 1H, J=8.65 Hz), 7.16 (d,1H, J=8.56 Hz), 6.33 (d,1H,J=5.71 Hz), 3.94 (s,1H), 3.00 (d,1H, J6.42 Hz), 2.39 (s,3H), 1.97-1.90(m, 1H), 0.87 (d, 6H, J=6.78 Hz) MS (ES+,M/Z) 467 (M+H),(ES−,m/z) 465(M−H).

Example 31N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]acetamide

HNMR: δ 12.70 (s, 1H), 9.79 (s, 1H), 9.15 (s, 1H), 7.99 (s, 3H), 7.95(s, 1H), 7.82 (d, 1H), 7.78 (d, 1H), 7.41 (s, 1H), 7.40 (s, 1H), 7.04(dd, 1H), 7.01 (dd, 1H), 5.76 (d, 1H), 3.48 (s, 3H), 3.33 (s, 3H), 2.01(s, 3H); MS (ES+, m/z)=388 (M+H).

Example 32N[3-({4-[ethyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]acetamide

HNMR: δ 12.67 (s, 1H), 9.73 (s, 1H), 9.09 (s, 1H), 7.76 (s, 1H), 7.83(d, 1H), 7.74 (d, 1H), 7.34 (s, 1H), 7.32 (d, 1H), 6.45 (dd, 1H), 6.41(dd, 2H), 5.76 (d, 1H), 3.97 (q, 1H), 3.47 (s, 3H), 3.33 (s, 3H), 2.13(s, 3H); MS (ES+, m/z)=402 (M+H).

Example 33N²-(2-methoxy-5-[(5-methyl-3-isoxazolyl)methyl]sulfonyl}phenyl)-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR (400 MHz, d₆-DMSO) δ 12.34 (br s, 1H), 9.63 (br s,1H), 8.77-8.75(m,1H),8.08 (d,1H, J=5.79 Hz), 7.90 (br s, 1H), 7.78 (brs,1H), 7.41(dd,1H, J=2.12 Hz and J=8.61 Hz), 7.24 (d, 1H, J=8.75 Hz), 7.19 (br s,1H), 6.38 (d, 1H, J=5.93 Hz), 6.14 (s, 1H), 4.64 (s, 2H), 3.98 (s, 3H),2.42 (s,3H), 2.34 (s,3H), MS (ES+, m/z) 506 (M+H).

Example 344-methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

HNMR (400 MHz, d₆-DMSO) δ 12.28 (br s, 1H), 9.56 (br s, 1H), 8.72 (br s,1H), 8.02 (d, 1H, J=5.71 Hz), 7.87 (br s, 1H), 7.74 (br s, 1H), 7.55 (d,1H, J=8.74 Hz), 7.43 (d, 1H, J=8.03 Hz), 7.17-7.13 (m, 4H), 6.32 (d, 1H,J=5.89 Hz), 3.91 (s, 3H), 2.39 (s, 3H), MS (ES, m/z) 424 (M−H).

Example 35N²-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

¹H NMR (400 MHz, d₆₋DMSO) δ 12.71 (br s, 1H), 9.03 (s, 1H), 7.83-7.79(m, 2H), 7.78 (d, J=8.4 Hz, 1H), 7.40-7.38 (m, 2H), 7.22 (d, J=8.6 Hz,1H), 6.9 (d, J=8.4 Hz, 1H), 5.74 (d, J=6.1 Hz, 1H), 3.95 (s, 3H), 3.47(s, 3H), 3.24 (m, 1H), 2.45 (s, 3H), 1.11 (d, J=6.7 Hz, 6H). MS (ES+,m/z) 467 (M+H).

Example 36N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-isopropyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

HNMR: δ 12.69 (s, 1H), 9.18 (s, 1H), 7.78 (s, 1H), 7.76 (d, 1H), 7.69(d, 1H), 7.57 (d, 1H), 7.22 (s, 1H), 6.86 (d, 1H), 6.82 (d, 1H), 5.26(d, 1H), 5.24 (m, 1H), 4.28 (q, 2H), 2.87 (s, 3H), 2.44 (s, 3H), 1.31(t, 3H), 1.08 (d, 6H); MS (ES+, m/z)=481 (M+H).

Example 37N-(1H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine

HNMR (400 MHz, d₆-DMSO) δ 13.15 (br s, 1H), 9.25 (br s, 1H), 8.10 (br s,1H), 7.87-7.80 (m, 3H), 7.66 (d. 1H, J=9.74 Hz), 7.47 (s, 1H), 7.13 (t,1H, J=7.90 Hz), 7.04 (d, 1H, J=8.33 Hz), 6.89 (d, 1H, J=7.34 Hz), 5.82(d, 1H, J=5.93 Hz), 4.29 (s, 2H), 3.49 (s, 3H), 2.88 (s, 3H), MS (AP+,m/z) 409 (M+H).

Example 38N⁴-(1,3-dimethyl-1H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine

To a solution ofN⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine(Example 23) (389 mg, 0.92 mmol) in DMF (4 ml) was added Cs₂CO₃ (600 mg,1.84 mmol) followed by iodomethane (64 ul, 1.02 mmol). The mixture wasstirred at rt overnight. The mixture was diluted with water andextracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered and evaporated. Purification of crude product byprep TLC provided 260 mg ofN⁴-(1,3-dimethyl-1H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]-phenyl}-2,4-pyrimidinediamine.¹H NMR (300 MHz, d₆DMSO) δ 9.25 (s, 1H), 7.86 (d, J=6.0 Hz, 1H), 7.82(s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.58 (s, 1H),7.15 (t, J=7.8 Hz, 1H), 7.02 (d, J=8.5 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H),5.83 (d, J=6.0 Hz, 1H), 4.28 (s, 2H), 3.92 (s, 3H), 3.49(s, 3H), 2.87(s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 437 (M+H).

Example 39N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine

To a solution ofN⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine(Example 23) (389 mg, 0.92 mmol) in DMF (4 ml) was added Cs₂CO₃ (600 mg,1.84 mmol) followed by iodomethane (64 ul, 1.02 mmol). The mixture wasstirred at rt overnight. The mixture was diluted with water andextracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered and evaporated. Purification of crude product byprep TLC provided 120 mgN⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]-phenyl}-2,4-pyrimidinediamine.¹H NMR (300 MHz, d₆DMSO) δ 9.23 (s, 1H), 7.84-7.86 (m, 2H), 7.74 (d,J=8.8 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.42 (s, 1H), 7.18 (t, J=7.8 Hz,1H), 6.85-6.90 (m, 2H), 5.81 (d, J=5.8 Hz, 1H), 4.23 (s, 2H), 4.04 (s,3H), 3.45 (s, 3H), 2,83 (s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 437 (M+H).

Example 40N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-2,4-pyrimidinediamine

This example was prepared using procedures similar to those of Example39. ¹H NMR (300 MHz, d₆DMSO) δ 9.15 (d, J=1.9 Hz, 1H), 7.88 (d, J=6.1Hz, 1H), 7.79-7.81 (m, 2H), 7.47-7.50 (m, 2H), 7.28 (d, J1 8.6 Hz, 1H),6.95 (d, J=8.7 (q, J=7.4 Hz, 2H), 2.65 (s, 3H), 1.13 (t, J=7.4 Hz, 3H).MS (ES+, m/z) 467 (M+H).

Example 411-[4-methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]-1-propanone

HNMR (400 MHz, d₆-DMSO) δ 12.45 (br s, 1H), 11.01 (br s, 1H), 9.90 (brs, 1H), 8.23 (s, 1H), 7.99 (d, 1H, J=6.78 Hz), 7.89 (d, 1H, J=7.33 Hz),7.59 (br s, 1H) 7.51 (d, 1H, J=6.78 Hz), 7.30-7.27 (m, 2H), 6.52 (s,1H), 3.93 (s, 3H), 2.66 (br, s, 2H), 2.43 (s, 3H), 0.85 (brs, 3H), MS(ES+, m/z) 403 (M+H).

Example 424-methoxy-N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]benzenesulfonamide

HNMR: δ 12.87 (s, 1H), 10.22 (s, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.78 (d,J=7.2 Hz, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.48 (s, 1H), 7.42 (s, 1H), 7.25(d, J=7.7 Hz, 1H), 7.04 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.5 Hz, 1H), 6.80(d, J=8.1 Hz, 1), 5.89 (d, J=7.2 Hz, 1H), 3.77 (s, 3H), 3.50 (s, 3H),2.51 (s, 3H); MS (ES+, m/z)=516, 517 (M+H).

Example 434-methoxy-N-methyl-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

HNMR (400 MHz, d₆-DMSO) δ 12.31 (s, 1H), 9.59 (s, 1H), 8.72 (s, 1H),8.03 (d,1H, J=5.71 Hz), 7.89 (br S, 1H), 7.72 (s, 1H), 7.54 (d, 1H,J=8.56 Hz), 7.36 (d, 1H, J=8.38 Hz), 7.28-7.22 (m, 1H), 7.19-7.15 (m,2H), 6.33 (d, 1H, J=5.89 Hz), 3.92 (s, 3H), 2.39 (s, 3H), 2.34 (d, 3H,J=4.99 Hz), MS (AP+, m/z) 440 (M+H).

Example 44[(3-methyl-1H-indazol-6-yl)(2-{4-[(methylsulfonyl)methyl]anilino}-4-pyrimidinyl)amino]acetonitrile

¹H NMR (300 MHz, d₆₋DMSO) δ 12.83 (br s, 1H), 9.52 (s, 1H), 7.97 (d,J=5.9 Hz, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.78 (d, J=8.5 Hz, 2H), 7.47 (s,1H) 7.27 (d, J=8.5 Hz, 2H), 7.03 (dd, J=8.5 & 1.5 Hz, 1H), 5.78 (d,J=5.9 Hz, 1H), 5.02 (s, 2H), 4.37 (s, 2H), 2.86 (s, 3H), 2.51 (s, 3H).MS (ES+, m/z) 448 (M+H).

Example 45[{2-[5-(ethylsulfonyl)-2-methoxyanilino]-4-pyrimidinyl}(3-methyl-1H-indazol-6-yl)amino]acetonitrile

¹H NMR (300 MHz, d₆₋DMSO) δ 12.85 (br s, 1H), 8.98 (d, J=2.2 Hz, 1H),8.08 (s, 1H), 8.00 (d, J=5.9 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.52-7.49(m, 2H), 7.29 (d, J1 8.8 Hz, 1H), 7.03 (dd, J=8.5 & 1.4 Hz, 1H), 5.80(d, J=5.9 Hz, 1H), 5.08 (s, 2H), 4.00 (s, 3H), 3.22 (q, J=7.3 Hz, 2H),2.51 (s, 3H), 1.12 (t, J=7.4 Hz, 3H). MS (ES+, m/z) 478 (M+H).

Example 46[(3-methyl-1H-indazol-6-yl)(2-{3-[(methylsulfonyl)methyl]anilino}-4-pyrimidinyl)amino]acetonitrile

¹H NMR (300 MHz, d₆₋DMSO) δ 12.83 (br s, 1H), 9.53 (s, 1H), 7.96 (m,2H), 7.86 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.47 (s, 1H), 7.26(t, J=7.8 Hz, 1H), 7.04-6.96 (m, 2H), 5.76 (d, J=5.8 Hz, 1H), 5.02 (s,2H), 4.39 (s, 2H), 2.90 (s, 3H), 2.51 (s, 3H). MS (ES+, m/z) 448 (M+H).

Example 474-methoxy-N-methyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (400 MHz, d₆DMSO) δ 12.70 (br s, 1H), 8.99 (d, J=2.2 Hz, 1H),7.74-7.80 (m, 3H), 7.32-7.36 (m, 2H), 7.15-7.18 (m, 2H), 6.97 (d, J=8.4Hz, 1H), 5.73 (d, J=6.0 Hz, 1H), 3.92 (s, 3H), 3.47 (s, 3H), 2.45 (s,3H), 2.36 (d, J=5.0 Hz, 3H). MS (ES+, m/z) 454 (M+H).

Example 484-({4-[methyl(3-methyl-1-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzamide

¹H NMR (300 MHz, d₆-DMSO) δ 12.72 (br s, 1H), 9.45 (s, 1H), 7.89 (d,J=6.0 Hz, 1H), 7.78-7.81 (m, 2H), 7.69-7.72 (m, 2H), 7.41 (s, 1H), 7.09(br s, 1H), 7.03 (d, J=8.5 Hz, 1H), 5.85 (d, J=6.0 Hz, 1H), 3.50 (s,3H), 2.50 (s, 3H). MS (ES+, m/z) 374 (M+H).

Example 493-methoxy-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (300 MHz, d₆DMSO) δ 12.92 (br s, 1H), 9.53 (d, J=2.2 Hz, 1H),7.97-8.04 (m, 2H), 7.91 (s, 1H), 7.59-7.64 (m, 2H), 7.34-7.38 (m, 3H),7.20 (dd, J=8.6 & 1.5 Hz, 1H), 5.96 (d, J=6.0 Hz, 1H), 4.14 (s, 3H),3.69 (s, 3H), 2.68 (s, 3H). MS (ES+, m/z) 440 (M+H).

Example 50N⁴-ethynyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine

¹H NMR (300 MHz, d₆-DMSO) δ 12.99 (br s, 1H), 9.57 (s, 1H), 8.08-8.10(m, 2H), 7.99 (d, J=8.4 Hz, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.63 (s, 11),7.38 (t, J=7.8 Hz, 1H), 7.19-7.23 (m, 1H), 7.12 (d, J=7.5 Hz, 1H), 5.94(d, J=4.7 Hz, 1H), 5.94 (s, 2H), 4.95 (s, 2H), 3.08 (s, 3H), 2.68 (s,3H). MS (ES+, m/z) 447 (M+H).

Example 513-({4-[(3-methyl-1H-indazol-6-yl)(2-propynyl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

HNMR (400 MHz, d₆₋DMSO): δ 12.76 (br s, 1H), 9.62 (s, 1H), 8.29 (br s,1H), 7.97 (br s, 1H), 7.92 (d, 1H, J=5.8), 7.81 (d, 1H, J=8.6), 7.45 (s,1H), 7.34 (d, 1H, J=4.2), 7.26 (s, 2H), 7.03 (d, 1H, J=8.4), 5.76 (d,1H, J=4.80 (s, 2H), 3.18 (s, 1H), 2.88 (m, 2H), 2.49 (s, 3H); MS (ES+,m/z)=455 (M+H).

Example 524-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (300 MHz, d₆DMSO) δ 12.91 (br s, 1H), 9.77 (s, 1H), 8.10 (d,=6.1Hz, 1H), 8.04 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.8Hz, 2H), 7.59 (s, 1H), 7.29 (br s, 2H), 7.20 (dd, J=8.5 & 1.5 Hz, 1H),6.08 (d, J=6.1 Hz, 1H), 3.68 (s, 3H), 2.69 (s, 3H). MS (ES+, m/z) 410(M+H).

Example 53N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-[3-(methylsulfonyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (300 MHz, d₆DMSO) δ 12.75 (br s, 1H), 9.65 (s, 1H), 8.69 (s, 1H),7.87-7.89 (m, 2H), 7.80 (d, J=8.4 Hz, 1H), 7.41 (m, 3H), 7.03 (d, J=8.2Hz, 1H), 5.82 (d, J=5.8 Hz, 1H), 3.52 (s, 3H), 3.16 (s, 3H), 2.51 (s,3H). MS (ES+, m/z) 409 (M+H).

Example 544-methoxy-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (300 MHz, d₆DMSO) δ 9.95 (br s, 1H), 8.73 (br s, 1H), 7.86-7.91(m, 2H), 7.68 (d, J=8.8 Hz, 1H), 7.55 (s, 1H), 7.30-7.34 (m, 3H), 7.08(d, J-8.5 Hz, 1H), 5.88 (d, J=7.4 Hz, 1H), 3.97 (s, 3H), 3.58 (s, 3H),2.52 (s, 3H). MS (ES+, m/z) 440 (M+H).

Example 55N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

¹HNMR (400 MHz, d₆-DMSO) δ 11.42 (br S, 1H), 10.19 (br s 1H), 7.96 (d,2H, J=7.14 Hz), 7.74 (dd, 1H, J=1.92 Hz and J=8.7 Hz), 7.53 (br s, 1H),7.39 (d, 1H, J8.79 Hz), 7.32 (br s, 1H), 6.64 (br s, 1H), 3.88 (s, 3H),2.96 (br s, 2H), 2.39 (s, 3H), 0.90 (br s, 3H), MS (ES−, m/z) 437 (M−H).

Example 563-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzamide

¹H NMR (300 MHz, d₆DMSO) δ 12.83 (s, 1H), 9.84 (br s, 1H), 8.29 (s, 1H),7.92-7.84 (m, 3H), 7.78 (d, J=7.7 Hz, 1H), 7.51-7.48 (m, 2H), 7.34-7.26(m, 2H), 7.07 (d, J=8.5 Hz, 1H), 5.89 (d, J=6.4 Hz, 1H), 3.55 (s, 3H),2.54 (s, 3H). MS (ES+, m/z) 374 (M+H).

Example 57N²-[4-(ethylsulfonyl)phenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, d₆-DMSO) δ 12.73 (s, 1H), 9.75 (s, 1H), 7.89-7.95 (m,3H), 7.81 (d, J=8.5 Hz, 1H), 7.58 (d, 3-=8.8 Hz, 2H), 7.41 (s, 1H), 7.03(dd, J=8.5 & 1.5 Hz, 1H), 5.96 (d, J=6.0 Hz, 1H), 3.50 (s, 3H), 3.16 (q,J=7.3 Hz, 2H), 2.52 (s, 3H), 1.07 (t, J=7.3 Hz, 3H). MS (ES+, m/z) 423(M+H).

Example 58N-[4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzyl]ethanesulfonamide

¹H NMR (400 MHz, d6-DMSO) δ 12.7 (s, 1H), 9.17 (s, 1H), 7.85 (d, J=6.0Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.47 (t, J=6.4Hz), 7.38 (s, 1H), 7.12 (d, J=8.4 Hz, 2H), 7.0 (dd, J=1.6 Hz, J=8.4 Hz,1H), 5.79 (d, J=6.0 Hz, 1H), 4.02 (d, J=6.2 Hz, 2H), 3.47 (s, 3H), 2.87(q, J=7.3 Hz, 2H), 2.51 (s, 3H), 1.13 (t, J=7.3 Hz, 3H).

Example 59N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzyl]methanesulfonamide

¹H NMR (400 MHz, d₆-DMSO) δ 12.7 (s, 1H), 9.21 (s, 1H), 7.84 (d, J=5.8Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.57 (d, J=7.8Hz, 1H), 7.48 (t, J=6.3 Hz, 1H), 7.38 (s, 1H), 7.12 (t, J=7.8 Hz, 1H),7.0 (dd, J=1.6 Hz, J =8.4 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 5.79 (d,J=5.8 Hz, 1H), 4.02 (d, J=6.2 Hz, 2H), 3.49 (s, 3H), 2.84 (2, 3H), 2.51(s, 3H).

Example 602-chloro-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (300 MHz, d₆-DMSO) δ 12.73 (s, 1H), 9.65 (s, 1H), 8.73 (d, J=2.1Hz, 1H), 7.79-7.87 (m, 2H), 7.34-7.46 (m, 3H), 7.02 (d, J=8.2 Hz, 1H),5.81 (d, J=6.0 Hz, 1H), 3.51 (s, 3H), 2.51 (s, 3H). MS (ES+, m/z) 444(M+H).

Example 612-chloro-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (300 MHz, d₆-DMSO) δ12.73 (s, 1H), 9.76 (s, 1H), 8.11 (s, 1H),7.95 (d, J=6.0 Hz, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.64-7.73 (m, 2H), 7.41(s, 1H), 7.33 (s, 2H), 7.03 (d, J=8.3 Hz, 1H), 5.95 (d, J=6.0 Hz, 1H),3.49 (s, 3H), 2.51 (s, 3H). MS (ES+, m/z) 444 (M+H).

Example 624-chloro-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (300 MHz, d₆-DMSO) δ 12.73 (s, 1H), 8.85 (d, 1-7 2.1 Hz, 1H),8.28 (s, 1H), 7.78-7.85 (m, 2H), 7.69 (d, J=8.4 Hz, 1H), 7.40-7.48 (m,4H), 7.01 (d, J=8.5 Hz, 1H), 5.80 (d, J=7.4 Hz, 1H), 3.46 (s, 3H), 2.50(s, 3H). MS (ES+, m/z) 444 (M+H).

Example 63

3-methyl-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (300 MHz, d₆-DMSO) δ 12.84 (br s, 1H), 9.33 (br s, 1H), 7.82-7.92(m, 3H), 7.69 (s, 1H), 7.59 (m, 1H), 7.46 (s, 1H), 7.27 (s, 2H), 7.04(dd, J=8.5 & 1.3 Hz, 1H), 5.90 (d, J=5.1 Hz, 1H), 3.46 (s, 3H), 2.51 (s,3H), 2.36 (s, 3H). 5 MS (ES+, m/z) 424 (M+H).

Example 642-methyl-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (300 MHz, d₆-DMSO) δ 12.71 (br s, 1H), 9.38 (s, 1H), 8.55 (s,1H), 7.67-7.87 (m, 3H), 7.37 (s, 1H), 7.21 (s, 1H), 7.11 (d, J=8.4 Hz,1H), 6.99 (d, J=8.5 Hz, 1H), 5.74 (d, J=5.8 Hz, 1H), 3.48 (s, 3H), 2.49(s, 3H), 2.47 (s, 3H).

MS (ES+, m/z) 424 (M+H).

Example 654-methyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide

¹H NMR (300 MHz, d₆-DMSO) δ 12.71 (br s, 1H), 10.25 (s, 1H), 8.30 (s,1H), 7.82-7.89 (m, 2H), 7.62 (d, J=7.9 Hz, 1H), 7.50-7.52 (m, 2H), 7.38(s, 2H), 7.05 (d, J=9.5 Hz, 1H), 5.84 (d, J=7.2 Hz, 1H), 3.46 (s, 3H),2.51 (s, 3H), 2.39 (s, 3H). MS (ES+, m/z) 424 (M+H).

Example 66N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-[3-(methylsulfinyl)phenyl]-2,4-pyrimidinediamine

¹H NMR (300 MHz, d₆-DMSO) δ 12.72 (s, 1H), 9.50 (s, 1H), 8.29 (s, 1H),7.89 (d, J=5.9 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.70 (d, J=7.9 Hz, 1H),7.40 (s, 1H), 7.33 (m, 1H), 7.12 (d, J=7.7 Hz, 1H), 7.07 (d, J=8.5 Hz,1H), 5.84 (d, J=6.0 Hz, 1H), 3.50 (s, 3H), 2.63 (s, 3H), 2.51 (s, 3H).MS (ES+, m/z) 393 (M+H).

Example 67N²-[2-fluoro-5-(methylsulfonyl)phenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine

¹H NMR (300 MHz, d₆-DMSO) 8 12.76 (br s, 1H), 9.07 (s, 1H), 8.89 (s,1H), 7.79-7.85 (m, 2H), 7.42-7.59 (m, 3H), 7.02 (m, 1H), 5.82 (m, 1H),3.48 (s, 3H), 3.20 (s, 3H), 2.50 (s, 3H). MS (ES+, m/z) 427 (M+H).

Example 68N²-[2-methoxy-5-(methylsulfonyl)phenyl]-N⁴-methyl-N⁴-(3-methyl-lindazol-6-yl)-2,4-pyrimidinediamine

HNMR: δ 12.74 (s, 1H), 9.13 (s, 1H), 7.85 (d, J=6.0 Hz, 1H), 7.80 (s,1H), 7.79 (d, J=10.3 Hz, 1H), 7.46 (dd, J=2.2, 8.6 Hz, 1H), 7.40 (s,1H), 7.24 (d, J=8.6 Hz, 1H), 7.00 (d, J=8.4 Hz, 1H), 5.78 (d, J=6.1 Hz,1H), 3.97 (s, 3H), 3.50 (s, 3H), 3.11 (s, 3H), 2.48 (s, 3H); MS (ES+,m/z)=439 (M+H).

Example 695-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzenesulfonamide

To a solution of Intermediate Example 13 (200 mg, 0.695 mmol) and5-amino-2-methylbenzenesulfonamide (129.4 mg, 0.695 mmol) in isopropanol(6 ml) was added 4 drops of conc. HCl. The mixture was heated to refluxovernight. The mixture was cooled to rt and diluted with ether (6 ml).Precipitate was collected via filtration and washed with ether. HCl saltof5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-pyrimidin-2-yl}amino)-2-methylbenzenesulfonamidewas isolated as an off-white solid. ¹H NMR (400 MHz, d₆DMSO+NaHCO₃) δ9.50 (br s, 1H), 8.55 (br s, 1H), 7.81 (d, J=6.2 Hz, 1H), 7.75 (d, J=8.7Hz, 1H), 7.69 (m, 1H), 7.43 (s, 1H), 7.23 (s, 2H), 7.15 (d, J=8.4 Hz,1H), 6.86 (m, 1H), 5.74 (d, J=6.1 Hz, 1H), 4.04 (s, 3H), 3.48 (s, 3H),2.61 (s, 3H), 2.48 (s, 3H). MS (ES+, m/z) 438 (M+H).

Examples 70-72 were prepared according to the general procedures setforth above in Example 69.

Example 703-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide

¹H NMR (400 MHz, d₆DMSO+NaHCO₃) δ 9.58 (br s, 1H), 8.55 (br s, 1H), 7.83(d, J=6.2 Hz, 1H), 7.74-7.79 (m, 2H), 7.43 (s, 1H), 7.34-7.37 (m, 2H),7.24 (s, 2H), 6.86 (m, 1H), 5.77 (d, J=6.1 Hz, 1H), 4.04 (s, 3H), 3.48(s, 3H), 2.61 (s, 3H). MS (ES+, m/z) 424 (M+H).

Example 712-[4-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)phenyl]ethanesulfonamide

¹H NMR (300 MHz, d₆DMSO+NaHCO₃) δ 9.10 (br s, 1H), 7.83 (d, J=6.0 Hz,1H), 7.75 (d, J=8.7 Hz, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.43 (d, J=1.1 Hz,1), 7.06 (d, J=8.5 Hz, 2H), 6.86-6.89 (m, 3H), 5.76 (d, J=6.0 Hz, 1H),4.06 (s, 3H), 3.46 (s, 3H), 3.21 (m, 2H), 2.91 (m, 2H), 2.62 (s, 3H). MS(ES+, m/z) 452 (M+H).

Example 72N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-N²-{4-[(methylsulfonyl)methyl]phenyl}pyrimidine-2,4-diamine

¹H NMR (300 MHz, d₆DMSO+NaHCO₃) δ 9.37 (bs, 1H), 7.88 (d, J=6.1 Hz, 1H),7.78 (m, 3H), 7.47 (s, 1H), 7.22 (d, J=8.5 Hz, 2H), 6.91 (dd, J=8.8, 1.5Hz, 1H), 5.84 (d, J=6.1 Hz, 1H), 4.37 (s, 2H), 4.09 (s, 3H), 3.51 (s,3H), 2.88 (s, 3H), 2.65 (s, 3H). MS (ES+, m/z) 437 (M+H), 435 (M−H).

Example 733-({4-[[3-(hydroxymethyl)-2-methyl-2H-indazol-6-yl](methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide

To a solution of 2,3-dimethyl-6-nitro-2H-indazole (3.00 g, 15.69 mmol)in CCl₄ (500 mL) was added AIBN (0.51 g, 3.14 mmol) and NBS (3.06 g,17.26 mmol). The mixture was heated to 80° C. for 5 hours then stirredat rt overnight. Approximately half of the solvent was removed in vacuo,and the mixture was filtered. The filtrate was conc. in vacuo, and thecrude product was purified by silica gel column chromatography elutingwith ethyl acetate and hexane to afford3-(bromomethyl)-2-methyl-6-nitro-2H-indazole with some succinimidepresent (4.41 g, 104% TY). ¹H NMR (300 MHz, CDCl₃) δ 8.68 (d, J=2.1 HZ,1H), 7.98 (dd, J=9.3, 2.1 Hz, 1H), 7.74 (d, J=9.3 Hz, 1H), 4.87 (s, 2H),4.28 (s, 3H). MS (ES+, m/z) 270, 272 (M+H).

3-(Bromomethyl)-2-methyl-6-nitro-2H-indazole (4.20 g, ˜14.9 mmol) inCH₃CN (500 ml) and water (200 ml) was treated with NaOH to give pH˜11.The solution was stirred at rt for 2 days then conc. in vacuo andrepeatedly extracted with dichloromethane and chloroform. The combinedorganic extracts were evaporated, and the crude product was purified bysilica gel column chromatography to give(2-methyl-6-nitro-2H-indazol-3-yl)methanol (1.03 g, 33% TY). MS (ES+,m/z) 208.

Under anhydrous conditions and nitrogen atmosphere, give(2-methyl-6-nitro-2H-indazol-3-yl)methanol (1.03 g, 4.97 mmol) in CH₂Cl₂(50 ml) was treated with triethylamine (0.58 g, 5.47 mmol) and DMAP (64mg, 0.50 mmol) followed by chlorotriphenylmethane (1.42 g, 5.07 mmol).The resulting solution was stirred under nitrogen at rt for 20 hoursthen diluted with CH₂Cl₂ and washed with water. Concentration in vacuofollowed by silica gel chromatography eluting with CH₂Cl₂ provided2-methyl-6-nitro-3-[(trityloxy)methyl]-2H-indazole (1.09 g, 49% TY). ¹HNMR (300 MHz, CDCl₃) δ 8.66 (d, J=2.1 HZ, 1H), 7.88 (dd, J=9.3, 2.1 Hz,1H), 7.55 (d, J=9.3 Hz, 1H), 7.50 (m, 6H), 7.1-7-4 (m, 9H), 4.52 (s,2H), 4.13 (s, 3H). MS (ES+, m/z) 450 (M+H).

To a solution of 2-methyl-6-nitro-3-[(trityloxy)methyl]-2H-indazole(0.50 g, 1.11 mmol) in anhydrous THF under nitrogen atmosphere at 0° C.was added LiAlH₄ (2.7 ml, 1.0 M in THF, 2.7 mmol). The solution wasstirred at 0° C. for ˜3 h then cooled to −78° C. and quenched with wetTHF. The resulting mixture was conc. in vacuo then repeatedly trituratedwith CH₃CN. The combined CH₃CN was conc. in vacuo to give crude2-methyl-3-[(trityloxy)methyl]-2H-indazol-6-amine (0.593 g, 108% TY). MS(ES+, m/z) 420 (M+H).

2-Methyl-3-[(trityloxy)methyl]-2H-indazol-6-amine was utilized in themanner described above for Intermediate Example 12 and 13 and accordingto the general procedures set forth above for Example 69. Purificationby preparative HPLC and isolation by lyophilization provided thetrifluoroacetate salt of3-({4-[[3-(hydroxymethyl)-2-methyl-2H-indazol-6-yl](methyl)amino]pyrimidin-2-yl}amino)-benzenesulfonamideas a tan solid. ¹H NMR (300 MHz, d₆DMSO+NaHCO₃) δ 9.53 (s, 1H), 8.57 (s,1H), 7.85 (m, 2H), 7.79 (d, J=7.2 Hz, 1), 7.51 (s, 1H), 7.36 (m, 2H),7.25 (s, 1H), 6.95 (d, J=8.9 Hz, 1H), 5.78 (d, J=6.0 Hz, 1H), 5.47 (t,J=5.4 Hz, 1H), 4.92 (d, J=5.4 Hz, 2H), 4.14 (s, 3H), 3.50 (s, 3H). MS(ES+, m/z) 440 (M+H), 438 (M−H).

Example 743-({4-[(1,2-dimethyl-1H-benzimidazol-5-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide

Intermediate Example 21 (200 mg) was combined with 100 mg of3-aminobenenesulfonamide in 5.0 mL of isopropanol with 3 drops ofaqueous HCl. The reaction was heated to 80° C. and followed by TLC. Whenthe reaction was judged to be complete based upon consumption theIntermediate Example 21, the reaction was quenched with solid sodiumbicarbonate while warm, then allowed to cool to room temperature. Thecomplete reaction mixture was then coated onto silica gel andchromatographed on silica gel using CH₂Cl₂ and MeOH as eluent affording223 mg of product. 1H NMR (400 MHz, d₆DMSO) δ 9.50 (s, 1H), 8.59 (s,1H), 7.80 (d, J=6.06 Hz, 1H), 7.77 (s, 1H), 7.57 (d, J=8.56 Hz, 1H),7.46 (d, J=1.78 Hz, 1H), 7.35 (m, 2H), 7.25 (s, 2H), 7.12 (dd, J=8.38,1.96 Hz, 1H), 5.62 (d, J=5.71 Hz, 1H), 3.76 (s, 3H), 3.48 (s, 3H), 2.54(s, 3H). MS (ESI) (M+H)⁺ 424.

Example 753-({4-[(2-benzyl-1-methyl-1H-benzimidazol-5-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide

Example 75 was prepared by the similar procedure set forth at theExample 74 wherein Intermediate Example 18 was used instead ofIntermediate Example 17 for the synthesis of Intermediate Example 21. 1HNMR (400 MHz, d₆DMSO) δ 9.49 (s, 1H) 8.57 (s, 1H) 7.79 (d, J=6.06 Hz,1H) 7.76 (m, 1H) 7.57 (d, J=8.56 Hz, 1H) 7.52 (d, J=1.78 Hz, 1H) 7.30(m, 5H) 7.22 (m, 4H) 7.14 (dd, J=8.38, 1.96 Hz, 1H) 5.64 (d, J=5.71 Hz,1H) 4.31 (s, 2H) 3.72 (s, 3H) 3.47 (s, 3H).

Example 763-({4-[(2-ethyl-3-methyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide

Example 76 was prepared according to the general procedure outlined inExample 69 wherein triethyloxonium hexafluorophosphate was used insteadof trimethyloxonium tetrafluoroborate in the synthesis of IntermediateExample 11. ¹H NMR (400 MHz, d₆DMSO) δ 8.39 (br s, 1H), 7.83 (m, 2H),7.73 (m, 1H), 7.49-7.55 (m, 3H), 7.36 (s, 2H), 6.90 (d, J=8.6 Hz, 1H),5.90 (m, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.52 (s, 3H), 2.64 (s, 3H), 1.42(t, J=7.1 Hz, 3H). MS (ES+, m/z) 438 (M+H).

Example 773-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide

Intermediate Example 9 (10 g, 0.029 mol) was treated with excesstrifluoroacetic acid (20 ml) at rt for 30 min. The reaction mixture wasquenched with NaHCO₃ and extracted with ethyl acetate. The organic layerwas separated, and the aqueous layer was thoroughly extracted withEtOAc. The combined organic layer was dried over anhydrous MgSO₄,filtered and evaporated to giveN-(2-chloropyrimidin-4-yl)-N,3-dimethyl-1H-indazol-6-amine as anoff-white solid (7.3 g, 100%). ¹H NMR (300 MHz, d₆DMSO) δ 12.80 (br s,1H), 7.94 (d, J=6.0 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.44 (s, 1H), 7.01(m, 1H), 6.25 (d, J=6.0 Hz, 1H), 3.42 (s, 3H), 2.50 (s, 3H). MS (ES+,m/z) 274 (M+H).

N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-1H-indazol-6-amine (2 g, 7.31mmol) was dissolved in DMF (15 ml), and Cs₂CO₃ (2 g, 14.6 mmol) and3-chlorobenzyl bromide (1.25 ml, 9.5 mmol) were added at roomtemperature. Mixture was stirred at rt for overnight. The reactionmixture was diluted with ethyl acetate and washed with water. Theorganic layer was separated. The aqueous layer was thoroughly extractedwith EtOAc. The combined organic layers were dried over anhydrous MgSO₄,filtered and evaporated to give2-(3-chlorobenzyl)-N-2-chloropyrimidin-4-yl)-N,3-dimethyl-2H-indazol-6-amineas an off-white solid. ¹H NMR (300 MHz, d₆DMSO) δ 7.94 (d, J=6.0 Hz,1H), 7.83 (d, J=8.8 Hz, 1H), 7.56 (d, J=1.3 Hz, 1H), 7.36-7.38 (m, 2H),7.32 (br s, 1H), 7.16 (m, 1H), 6.91 (m, 1H), 6.28 (d, J=6.1 Hz, 1H),5.65 (s, 2H), 3.42 (s, 3H), 2.63(s, 3H). MS (ES+, m/z) 398 (M+H).

To a solution of2-(3-chlorobenzyl)-N-(2-chloropyrimidin-4-yl)-N,3-dimethyl-2H-indazol-6-amine(40 mg, 0.1 mmol) and 3-aminobenzenesulfonamide (17.3 mg, 0.1 mmol) inisopropanol (2 ml) was added 2 drops of conc. HCl. The mixture washeated to reflux overnight. The mixture was cooled to rt. Precipitatewas collected via filtration and washed with EtOH. HCl salt of3-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]-pyrimidin-2-yl}amino)benzenesulfonamidewas isolated as off-white solid. ¹H NMR (400 MHz, d₆DMSO+NaHCO₃) δ 9.52(br s, 1H), 8.54 (br s, 1H), 7.85 (d, J=5.9 Hz, 1H), 7.77-7.79 (m, 2H),7.49 (s, 1H), 7.30-7.36 (m, 5H), 7.22 (br, s, 2H), 7.14 (br s, 1H), 6.90(d, J=8.7 Hz, 1H), 5.80 (d, J=5.8 Hz, 1H), 5.64 (s, 2H), 3.48 (s, 3H),2.62 (s, 3H). MS (ES+, m/z) 534 (M+H).

Example 783-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino-]1,3,5-triazin-2-yl}amino)benzenesulfonamide

Intermediate Example 15 (0.017 g, 0.06 mmol), and3-aminobenzenesulfonamide (0.01 g, 0.06 mmol) were combined in EtOH. A1N solution of HCl in diethylether was added (0.06 mL, 0.06 mmol), andthe solution was warmed to reflux for 18 h. The solution was cooled toRT, and the precipitate was filtered off, washed with EtOH, and dried,to give analytically pure product as a white solid (0.025 g ). ¹H NMR(300 MHz, d₆DMSO) δ 9.99 (br s, 1H), 8.24 (br s, 1H), 7.80 (d, J=6.4Hz,₁ H), 7.68 (d, J=8.0 Hz, 1H), 7.40-7.46 (m, 2H), 7.27-7.33 (m, 2H),6.93 (d, J=7.7 Hz, 1H), 4.05 (s, 3H), 3.51 (s, 3H), 2.62 (s, 3H). MS(ES+, m/z) 425 (M+H).

Example 795-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-1,3,5-triazin-2-yl}amino)-2-methylbenzenesulfonamide

Intermediate Example 15 (0.032 g, 0.11 mmol), and3-amino-4-methylbenzenesulfonamide (0.021 g, 0.11 mmol) where combinedin EtOH. A 1N solution of HCl in diethylether was added (0.06 mL, 0.06mmol), and the solution was warmed to reflux for 18 h. The solution wascooled to RT, and the precipitate was filtered off, washed with EtOH,and dried, to give analytically pure product as a tan solid (0.033 g ).¹H NMR (300 MHz, d₆DMSO) δ 9.88 (br s, 1H), 8.19 (br s, 1H), 7.70-7.65(m, 2H), 7.41 (s, 1H), 7.28 (brs, 2H), 6.90 (d, J=8.8 Hz, 1H), 4.04 (s,3H), 3.50 (s, 3H), 2.61 (s, 3H), 2.49 (s, 3H). MS (ES+, m/z) 439 (M+H).

Biological Data

The compounds of the present invention elicit important and measurablepharmacological responses. Each of the compounds described in theExamples section bind with high affinity (IC₅₀<1 μM) to the kinasedomain of VEGFR2 receptor, as described by the VEGFR2 HTRF assay below.In addition to binding to the kinase domain of VEGFR2, the exemplifiedcompounds of the present invention also measurably and significantlyinhibit the proliferation of endothelial cells that are stimulated forgrowth by activation with VEGF. Data for inhibition of cellproliferation are provided in Table 1 below.

VEGFR2 HTRF Assay

The assays were performed in 96-well black plates. 10 nM hVEGFR2 wasused to phosphorylate 0.36 AM peptide (Biotin-Ahx-EEEEYFELVAKKKK) in thepresence of 75 μM ATP, 5 mM MgCl₂, 0.3 mM DTT, 0.1 mg/ml BSA, and 0.1 MHEPES (pH 7.5). 10 μl 10.5 M EDTA was added to reactions as negativecontrols. The 50 μl kinase reaction with or without inhibitors in 5%DMSO was carried out at room temperature for 45 minutes, then stopped by40 μl of 125 mM EDTA. 2.4 μg/ml Streptavidin-APC and 0.15 μg/ml Eu-α-pY,in the presence of 0.1 mg/ml BSA, 0.1 M HEPES (pH7.5), were added to afinal volume of 140 μl. The plate was incubated for 10 min at roomtemperature (22° C.) and read on the Victor with the time resolvedfluorescence mode by exciting at 340 nm and reading the emission at 665nm.

Reagent Resources:

Peptide from Synpep (Dublin, Calif.)

ATP, MgCl₂, DTF, BSA, HEPES, EDTA, DMSO from Sigma

Streptavidin-APC from Molecular Probes (Eugene, Oreg.)

Eu-α-pY from E.G.&G Wallac (Gaithersburg, Md.) Abbreviations: ATPAdenosine Triphosphate Streptavidin-APC Streptavidin, allophycocyanine,crosslinked conjugate DMSO Dimethyl Sulfoxide DTT Dithiothreitol BSABovine Serum Albumin HTRF Homogenous Time Resolved Fluorescence EDTAEthylenedinitrilo Tetraacetic Acid HEPES N-2-Hydroxyethyl PiperazineN-Ethane Sulfonic Acid Eu-α-pY Europium labeled anti-phosphotyrosineantibodyHuman Umbilical Vein Endothelial Cell (HUVEC) Proliferation Assay (BrdUIncorporation)Materials

HUVEC cells and EGM-MV (Endothelial cell growth medium—microvascular)were purchased from Clonetics (San Diego, Calif.). VEGF and bFGF werepurchased from R&D Systems (Minneapolis, Minn.). Anti-BrdU antibody wasobtained from Chemicon International (Temecula, Calif.).

Methods

HUVECs were routinely maintained in EGM-MV medium and were used withinpassage 7. HUVECs were plated at a density of 2500 cells/well in M199medium containing 5% FBS (Hyclone) in type I collagen coated plate(Becton Dickinson). The plate was incubated at 37° C. overnight. Themedium was removed by aspiration, and test compounds were added to eachwell in a volume of 0.1 ml/well in serum-free M199 medium. Compoundconcentrations ranged from 1.5 nM to 30 micromolar. The plate wasincubated for 30 min at 37° C. Another 0.1 ml of serum-free M199 mediumcontaining BSA and VEGF (or bFGF) was added to give a finalconcentration of 0.1% BSA and 10 ng/ml VEGF (0.3 ng/ml bFGF). The platewas incubated at 37° C. for 72 hrs. BrdU was added to each well afterthe first 48 hrs to give a concentration of 10 micromolar. Thecalorimetric ELISA assay was performed according to manufacturer's(Roche Molecular Sciences) instructions, with detection by absorbancereading at 450 nm. Results were plotted as concentration of testcompound vs. absorbance to give an IC₅₀ value for inhibition of BrdUincorporation.

Table 1=Inhibition of HUVEC proliferation (IC₅₀ in nM; 1-2-00 nM=++++;201-500 nM=+++; 501-1000 nM=++; >1,000=+) TABLE 1 Example No. IC₅₀ 1 +++2 ++++ 3 ++++ 4 +++ 5 +++ 6 +++ 7 +++ 8 +++ 9 +++ 10 + 11 +++ 12 ++++ 13+++ 14 ++++ 15 ++ 16 +++ 17 ++ 18 ++ 19 +++ 20 + 21 ++++ 22 ++++ 23 ++++24 ++++ 25 ++++ 26 +++ 27 ++++ 28 ++++ 29 ++++ 30 ++ 31 ++++ 32 ++++33 + 34 +++ 35 ++++ 36 + 37 +++ 38 +++ 39 ++++ 40 ++++ 41 ++ 42 +++ 43+++ 44 +++ 45 ++ 46 ++++ 47 +++ 48 ++++ 49 ++++ 50 +++ 51 +++ 52 ++++ 53++++ 54 ++++ 55 ++++ 56 ++++ 57 +++ 58 ++++ 59 ++++ 60 ++++ 61 +++ 62++++ 63 +++ 64 ++++ 65 ++++ 66 ++++ 67 +++ 68 ++++ 69 ++++ 70 ++++ 71++++ 72 ++++ 73 ++++ 74 ++++ 75 ++++ 76 ++++ 77 ++++ 78 ++++ 79 +++

The application of which this description and claim(s) forms part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described herein. They may take the form ofproduct, composition, process or use claims and may include, by way ofexample and without limitation, one or more of the following claim(s):

1. A compound of Formula (I):

or a salt or solvate thereof: wherein: D is

X₁ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, or C₁₋C₄ hydroxyalkyl; X₂is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C(O)R¹, or aralkyl; X₃ ishydrogen or halogen; X₄ is hydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl,heteroaralkyl, cyanoalkyl, —(CH₂)_(p)C═CH(CH₂)_(t)H,—(CH₂)_(p)C≡C(CH₂)_(t)H, or C₃-C₇ cycloalkyl; p is 1, 2, or 3; t is 0 or1; W is N or C—R, wherein R is hydrogen, halogen, or cyano; Q, ishydrogen, halogen, C₁-C₂ haloalkyl, C₁-C₂ alkyl, C₁-C₂ alkoxy, or C₁-C₂haloalkoxy; Q₂ is A¹ or A²; Q₃ is A¹ when Q₂ is A² and Q₃ is A² when Q₂is A¹; wherein A¹ is hydrogen, halogen, C₁-C₃ alkyl, C₁-C₃ haloalkyl,—OR¹, and A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z isCH₂ and m is 0, 1, 2, or 3, or Z is NR²and m is 0 or 1, or Z is oxygenand m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂, S(O), orC(O); and Z² is C₁-C₄alkyl, NR³R⁴, aryl, arylamino, aralkyl, aralkoxy,or heteroaryl, R¹ is C₁-C₄ alkyl; R², R³, and R⁴ are each independentlyselected from hydrogen, C₁₋C₄ alkyl, C₃₋C₇ cycloalkyl, —S(O)₂R⁵, and—C(O)R⁵; R⁵ is C₁₋C₄ alkyl, or C₃₋C₇ cycloalkyl; and when Z is oxygenthen Z¹ is S(O)₂ and when D is

then X₂ is C₁-C₄ alkyl, C₁-C₄ haloalkyl, C(O)R¹, or aralkyl.
 2. Acompound as claimed in claim 1 wherein D is


3. A compound as claimed in claim 1: wherein D is


4. A compound of claim 1: wherein D is


5. A compound of formula (II):

or a salt or solvate thereof: wherein: X₁ is hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl, or C₁₋C₄ hydroxyalkyl; X₂ is hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C(O)R¹, or aralkyl; X₃ is hydrogen or halogen; X₄ ishydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, heteroaralkyl, cyanoalkyl,—(CH₂)_(p)C═CH(CH₂)_(t)H, —(CH₂)_(p)C═C(CH₂)_(t)H, or C₃-C₇ cycloalkyl;p is 1, 2, or 3; t is 0 or 1; W is N or C—R, wherein R is hydrogen,halogen, or cyano; Q₁ is hydrogen, halogen, C₁-C₂ haloalkyl, C₁-C₂alkyl, C₁-C₂ alkoxy, or C₁-C₂ haloalkoxy; Q₂ is A¹ or A²; Q₃ is A¹ whenQ₂ is A² and Q₃ is A² when Q₂ is A¹; wherein A¹ is hydrogen, halogen,C₁-C₃ alkyl, C₁-C₃ haloalkyl, —OR¹, and A² is the group defined by-(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z is NR²and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH₂NR²and m is0 or 1; Z¹ is S(O)₂, S(O), or C(O); and Z² is C₁₋C₄alkyl, NR³R⁴, aryl,arylamino, aralkyl, aralkoxy, or heteroaryl, R¹ is C₁-C₄alkyl; R², R³,and R⁴ are each independently selected from hydrogen, C₁₋C₄ alkyl, C₃₋C₇cycloalkyl, —S(O)₂R⁵, and —C(O)R⁵; R⁵ is C₁₋C₄ alkyl, or C₃₋C₇cycloalkyl; and when Z is oxygen then Z¹ is S(O)₂.
 6. A compound ofFormula (III):

or a salt or solvate thereof: wherein: X₁ is hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl, or C₁₋C₄ hydroxyalkyl; X₂ is C₁-C₄ alkyl, C₁-C₄haloalkyl, or C(O)R¹; X₃ is hydrogen or halogen; X₄ is hydrogen, C₁-C₄alkyl, C₁-C₄ haloalkyl, heteroaralkyl, cyanoalkyl,—(CH₂)_(p)C═CH(CH₂)_(t)H, —(CH₂)_(p)C≡C(CH₂)_(t)H, or C₃-C₇ cycloalkyl;p is 1, 2, or 3; t is 0 or 1; W is N or C—R, wherein R is hydrogen,halogen, or cyano; Q₁ is hydrogen, halogen, C₁-C₂ haloalkyl, C₁-C₂alkyl, C₁-C₂ alkoxy, or C₁-C₂ haloalkoxy; Q₂ is A¹ or A²; Q₃ is A¹ whenQ₂ is A² and Q₃ is A² when Q₂ is A¹; wherein A¹ is hydrogen, halogen,C₁-C₃ alkyl, C₁-C₃ haloalkyl, —OR¹, and A² is the group defined by-(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z is NR²and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH₂NR² and m is0 or 1; Z¹ is S(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl, NR R⁴, aryl,arylamino, aralkyl, aralkoxy, or heteroaryl, R is C₁₋C₄ alkyl; R², R³,and R⁴ are each independently selected from hydrogen, C₁₋C₄ alkyl, C₃₋C₇cycloalkyl, —S(O)₂R⁵, and —C(O)R⁵; R⁵ is C₁₋C₄ alkyl, or C₃₋C₇cycloalkyl; and when Z is oxygen then Z¹ is S(O)₂.
 7. A compound ofFormula (IV):

or a salt or solvate thereof; wherein: X₁ is hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl, or C₁₋C₄ hydroxyalkyl; X₂ is hydrogen, C₁-C₄ alkyl,C₁-C₄ haloalkyl, or C(O)R¹, or aralkyl; X₃ is hydrogen or halogen; X₄ ishydrogen, C₁-C₄ alkyl, C₁-C₄ haloalkyl, heteroaralkyl, cyanoalkyl,—(CH₂)_(p)C═CH(CH₂)_(t)H, —(CH₂)_(p)C≡C(CH₂)_(t)H, or C₃-C₇ cycloalkyl;p is 1, 2, or 3; t is 0 or 1; W is N or C—R, wherein R is hydrogen,halogen, or cyano; Q₁ is hydrogen, halogen, C₁-C₂ haloalkyl, C₁-C₂alkyl, C₁-C₂ alkoxy, or C₁-C₂ haloalkoxy; Q₂ is A¹ or A²; Q₃ is A¹ whenQ₂ is A²and Q₃ is A²when Q₂is A¹; wherein A¹ is hydrogen, halogen,C₁-C₃alkyl, C₁-C₃ haloalkyl, —OR¹, and A² is the group defined by-(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or3, or Z isNR²and m is 0 or 1, or Z is oxygen and m is 0 or 1, or Z is CH₂NR²and mis 0 or 1; Z¹ is S(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl, NR³R⁴,aryl, arylamino, aralkyl, aralkoxy, or heteroaryl, R¹ is C₁-C₄ alkyl;R², R³, and R⁴ are each independently selected from hydrogen, C₁₋C₄alkyl, C₃₋C₇ cycloalkyl, —S(O)₂R⁵, and —C(O)R⁵; R⁵ is C₁₋C₄ alkyl, orC₃₋C₇ cycloalkyl; and when Z is oxygen then Z¹ is S(O)₂.
 8. A compoundas claimed in claim 1, wherein X₁ is hydrogen or C₁₋₄ alkyl.
 9. Acompound as claimed in claim 1, wherein X₁ is methyl or ethyl.
 10. Acompound as claimed in claim 1, wherein X₁ is methyl.
 11. A compound asclaimed in claim 1, wherein X₂ is hydrogen or C₁₋₄ alkyl.
 12. A compoundas claimed in claim 1, wherein X₂ is hydrogen or methyl.
 13. A compoundas claimed in claim 1, wherein X₂ is hydrogen.
 14. A compound as claimedin claim 1, wherein X₂ is methyl.
 15. A compound as claimed in claim 1,wherein X₃ is halogen.
 16. A compound as claimed in claim 1, wherein X₃is hydrogen.
 17. A compound as claimed in claim 1, wherein X₄ ishydrogen, C₁-C₄ alkyl, cyanoalkyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H.
 18. Acompound as claimed in claim 1, wherein X₄ is hydrogen, methyl, ethyl,isopropyl, cyanomethyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H, wherein p is 1 and tis
 0. 19. A compound as claimed in claim 1, wherein X₄ is methyl.
 20. Acompound as claimed in claim 1, wherein X₁ is methyl or ethyl, X₂ ishydrogen or methyl, X₃ is hydrogen or halogen, and X₄ is hydrogen,methyl, ethyl, isopropyl, cyanomethyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H,wherein p is 1 and t is
 0. 21. A compound as claimed in claim 1, whereinX₁ is methyl, X₂ is hydrogen, X₃ is hydrogen, and X₄ is methyl.
 22. Acompound as claimed in claim 1, wherein X₁ is methyl, X₂ is methyl, X₃is hydrogen, and X₄ is methyl.
 23. A compound as claimed in claim 1,wherein D is:

and X₁ is methyl, X₂ is hydrogen, X₃ is hydrogen, and X₄ is methyl. 24.A compound as claimed in claim 1, wherein D is

and X₁ is methyl, X₂ is methyl, X₃ is hydrogen, and X₄ is methyl.
 25. Acompound as claimed in claim 1, wherein W is N.
 26. A compound asclaimed in claim 1, wherein W is C—R wherein R is H, F, Cl, or CN.
 27. Acompound as claimed in claim 1, wherein W is N, C—H, or C—F.
 28. Acompound as claimed in claim 1, wherein W is C—F or C—H.
 29. A compoundas claimed in claim 1, wherein Q, is hydrogen, halogen, C₁₋C₂ alkyl orC₁₋C₂ alkoxy.
 30. A compound as claimed in claim 1, wherein Q₁ ishydrogen.
 31. A compound as claimed in claim 1, wherein Q₁ is chlorine.32. A compound as claimed in claim 1, wherein Q₁ is methyl.
 33. Acompound as claimed in claim 1, wherein Q₁ is methoxy.
 34. A compound asclaimed in claim 1, wherein Q₂ is A¹ and Q₃ is A².
 35. A compound asclaimed in claim 1, wherein Q₂ is A² and Q₃ is A¹.
 36. A compound asclaimed in claim 1, wherein Q₂ is A²and Q₃ is A¹, wherein A¹ ishydrogen, halogen, or C₁₋C₃ haloalkyl and A² is the group defined by-(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z is NR²and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂, S(O), orC(O); and Z² is C₁₋C₄ alkyl or NR³R⁴ and wherein R², R³, and R⁴ are eachindependently selected from hydrogen or C₁₋C₄alkyl.
 37. A compound asclaimed in claim 1, wherein Q₂ is A² and Q₃ is A¹, wherein A¹ ishydrogen or chlorine and A² is the group defined by -(Z)_(m)-(Z¹)-(Z²),wherein Z is CH₂ and m is 0, 1, 2, or 3; Z¹ is S(O)₂; and Z² is C₁₋C₄alkyl.
 38. A compound as claimed in claim 1, wherein Q₂ is A¹ and Q₃ isA², wherein A¹ is hydrogen, halogen, or C₁₋C₃ alkyl and A² is the groupdefined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3,or Z is NR² and m is 0 or 1, or Z is CH₂NR and m is 0 or 1; Z is S(O)₂,S(O), or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R², R³, andR⁴ are each independently selected from hydrogen or C₁₋C₄ alkyl.
 39. Acompound as claimed in claim 1, wherein Q₂ is A¹ and Q₃ is A², whereinA¹ is hydrogen, methyl, or chlorine and A² is the group defined by-(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3; Z¹ isS(O)₂; and Z² is C₁₋C₄ alkyl or NR³R⁴, wherein R³ and R⁴ are eachindependently selected from hydrogen or C₁₋C₄ alkyl.
 40. A compound asclaimed in claim 1, wherein X₁ is hydrogen or C₁₋₄ alkyl; X₂ is hydrogenor C₁₋₄ alkyl; X₃ is hydrogen or halogen; and X₄ is hydrogen, C₁-C₄alkyl, cyanoalkyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H; W is N; Q₁ is hydrogen,halogen, C₁₋C₂ alkyl or C₁₋C₂ alkoxy; and Q₂ is A² and Q₃ is A¹ ,wherein A¹ is hydrogen, halogen, or C₁₋C₃ haloalkyl and A² is the groupdefined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3,or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴ and wherein R², R³, and R⁴ areeach independently selected from hydrogen or C₁₋C₄alkyl.
 41. A compoundas claimed in claim 1, wherein X₁ is hydrogen or C₁₋₄ alkyl; X₂ ishydrogen or C₁₋₄ alkyl; X₃ is hydrogen or halogen; and X₄ is hydrogen,C₁-C₄ alkyl, cyanoalkyl, or —(CH₂)_(p)C=C(CH₂)_(t)H; W is C—R wherein Ris H, F, Cl, or CN; Q₁ is hydrogen, halogen, C₁₋C₂ alkyl or C₁₋C₂alkoxy; and Q₂ is A² and Q₃ is A¹ , wherein A¹ is hydrogen, halogen, orC₁₋C₃ haloalkyl and A² is the group defined by -(Z)_(m)-(Z¹)-(Z²),wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z is NR² and m is 0 or 1, orZ is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂ or C(O); and Z² is C₁₋C₄ alkylor NR³R⁴ and wherein R², R³, and R⁴ are each independently selected fromhydrogen or C₁₋C₄alkyl.
 42. A compound as claimed in claim 1, wherein X₁is hydrogen or C₁₋₄ alkyl; X₂ is hydrogen or C₁₋₄ alkyl; X₃ is hydrogenor halogen; and X₄ is hydrogen, C₁-C₄ alkyl, cyanoalkyl, or—(CH₂)_(p)C≡C(CH₂)_(t)H; W is N; Q₁ is hydrogen, halogen, C₁₋C₂ alkyl orC₁₋C₂ alkoxy; Q₂ is A¹ and Q₃ is A², wherein A¹ is hydrogen, halogen, orC₁₋C₃ alkyl and A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein Zis CH₂ and m is 0, 1, 2, or 3, or Z is NR² and m is 0 or 1, or Z isCH₂NR² and m is 0 or 1; Z¹ is S(O)₂, S(O), or C(O); and Z² is C₁₋C₄alkyl or NR³R⁴, and wherein R², R³, and R⁴ are each independentlyselected from hydrogen or C₁₋C₄ alkyl.
 43. A compound as claim in claim1, wherein X₁ is hydrogen or C₁₋₄ alkyl; X₂ is hydrogen or C₁₋₄ alkyl;X₃ is hydrogen or halogen; and X₄ is hydrogen, C₁-C₄ alkyl, cyanoalkyl,or —(CH₂)_(p)C≡C(CH₂)_(t)H.; W is C—R wherein R is H, F, Cl, or CN; Q,is hydrogen, halogen, C₁₋C₂ alkyl or C₁₋C₂ alkoxy; Q₂ is A¹ and Q₃ isA², wherein A¹ is hydrogen, halogen, or C₁₋C₃ alkyl and A² is the groupdefined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3,or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ isS(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R²,R³, and R⁴ are each independently selected from hydrogen or C₁₋C₄ alkyl.44. A compound as claimed in claim 1, wherein X₁ is methyl or ethyl; X₂is hydrogen or methyl; X₃ is hydrogen; and X₄ is hydrogen, methyl,ethyl, isopropyl, cyanomethyl, or —(CH₂)_(p)C≡C(CH₂)_(t)H, wherein p is1 and t is 0.; W is N, C—H, C—F, or C—CN; Q₁ is hydrogen, chlorine, ormethoxy; Q₂ is A¹ and Q₃ is A², wherein A¹ is hydrogen, methyl, orchlorine and A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z isCH₂ and m is 0, 1, 2, or 3, or Z is NR² and m is 0 or 1, or Z is CH₂NR²and m is 0 or 1; Z¹ is S(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl orNR³R⁴, and wherein R², R³, and R⁴ are each independently selected fromhydrogen or C₁₋C₄ alkyl.
 45. A compound as claimed in claim 1, whereinX₁ is methyl or ethyl; X₂ is hydrogen or methyl; X₃ is hydrogen; and X₄is hydrogen, methyl, ethyl, isopropyl, cyanomethyl, or—(CH₂)_(p)C≡C(CH₂)_(t)H, wherein p is 1 and t is 0.; W is C—H or C—F; Q₁is hydrogen, chlorine, methyl, or methoxy; Q₂ is A¹ and Q₃ is A²,wherein A¹ is hydrogen, methyl, or chlorine and A² is the group definedby -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z isNR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ is S(O)₂, S(O),or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R², R³, and R⁴ areeach independently selected from H or C₁₋C₄ alkyl.
 46. A compound asclaimed in claim 1, wherein X₁ is methyl; X₂ is hydrogen; X₃ ishydrogen; and X₄ is methyl; W is C—H; Q₁ is hydrogen, chlorine, methyl,or methoxy; Q₂ is A¹ and Q₃ is A², wherein A¹ is hydrogen, methyl, orchlorine and A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z isCH₂ and m is 0, 1, 2, or 3, or Z is NR 2and m is 0 or 1, or Z is CH₂NR²and m is 0 or 1; Z¹ is S(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl orNR³R⁴, and wherein R², R³, and R⁴ are each independently selected fromhydrogen or C₁₋C₄ alkyl.
 47. A compound as claimed in claim 1, whereinX₁ is methyl; X₂ is methyl; X₃ is hydrogen; and X₄ is methyl; W is C—H;Q₁ is hydrogen, chlorine, methyl, or methoxy; Q₂ is A¹ and Q₃ is A²,wherein A¹ is hydrogen, methyl, or chlorine and A² is the group definedby -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3, or Z isNR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ S(O)₂, S(O), orC(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R², R³, and R⁴ areeach independently selected from hydrogen or C₁₋C₄ alkyl.
 48. A compoundas claimed in claim 1, wherein X₁ is methyl; X₂ is hydrogen; X₃ ishydrogen; and X₄ is methyl; W is C—F; Q₁ is hydrogen, chlorine, ormethoxy; Q₂ is A¹ and Q₃ is A² ₁ wherein A¹ is hydrogen, methyl, orchlorine and A² is the group defined by -(Z)_(m)-(Z¹)-(Z²), wherein Z isCH₂ and m is 0, 1, 2, or 3, or Z is NR² and m is 0 or 1, or Z is CH₂NR²and m is 0 or 1; Z is S(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl orNR³R⁴, and wherein R², R³, and R⁴ are each independently selected fromhydrogen or C₁₋C₄ alkyl.
 49. A compound as claimed in claim 1, wherein Dis:

and X₁ is methyl; X₂ is hydrogen; X₃ is hydrogen; and X₄ is methyl; W isC—H; Q₁ is hydrogen, methyl, chlorine, or methoxy; Q₂ is A¹ and Q₃ isA², wherein A¹ is hydrogen, methyl, or chlorine and A² is the groupdefined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3,or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ isS(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R²,R³, and R⁴ are each independently selected from hydrogen or C₁₋C₄ alkyl.50. A compound as claimed in claim 1, wherein D is

and X₁ is methyl; X₂ is methyl; X₃ is hydrogen; and X₄ is methyl; W isC—H; Q₁ is hydrogen, chlorine, methyl, or methoxy; Q₂ is A¹ and Q₃ isA², wherein A¹ is hydrogen, methyl, or chlorine and A² is the groupdefined by -(Z)_(m)-(Z¹)-(Z²), wherein Z is CH₂ and m is 0, 1, 2, or 3,or Z is NR² and m is 0 or 1, or Z is CH₂NR² and m is 0 or 1; Z¹ isS(O)₂, S(O), or C(O); and Z² is C₁₋C₄ alkyl or NR³R⁴, and wherein R²,R³, and R⁴ are each independently selected from hydrogen or C₁₋C₄ alkyl.51. A compound selected from the group consisting of:N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-5-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-4-methoxy-N-methylbenzenesulfonamide;5-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-N-isopropylbenzenesulfonamide;5-fluoro-N²-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N-[5-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-2-methylphenyl]methanesulfonamide;5-fluoro-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-[4-(methylsulfonyl)phenyl]-2,4-pyrimidinediamine;N⁴-(3-ethyl-1H-indazol-6-yl)-5-fluoro-N²(-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;N⁴-ethyl-5-fluoro-N²-[2-methoxy-5-(methylsulfonyl)phenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;[4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]-N-methylmethanesulfonamide;5-fluoro-N²-{3-[(isopropylsulfonyl)methyl]phenyl}-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;3-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-4-methoxybenzamide;4-({5-fluoro-4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)-3-methoxybenzenesulfonamide;N²-(3-methyl-1H-indazol-6-yl)-N⁴-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diaminetrifluoroacetate;N²-methyl-N²-(3-methyl-1H-indazol-6-yl)-N⁴-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazine-2,4-diamine;N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-1,3,5-triazine-2,4-diamine;N-[2-methyl-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-1,3,5-triazin-2-yl}amino)phenyl]methanesulfonamide;N²-methyl-N²-(3-methyl-1H-indazol-6-yl)-N⁴-[3-(methylsulfonyl)phenyl]-1,3,5-triazine-2,4-diamine;N-[4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-1,3,5-triazin-2-yl}amino)phenyl]acetamide;3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;N-isopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;N-cyclopropyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;N⁴-ethyl-N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]methanesulfonamide;N²-{3-[(isopropylsulfonyl)methyl]phenyl}-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N²-{4-[(isopropylsulfonyl)methyl]phenyl}-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N²-[5-(isobutylsulfonyl)-2-methoxyphenyl]-N⁴(-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]acetamide;N-[3-({4-[ethyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]acetamide;N²-(2-methoxy-5-{[(5-methyl-3-isoxazolyly)methyl]sulfonyl}phenyl)-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;4-methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;N²-[5-(isopropylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-isopropyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N⁴-(1H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;N⁴-(1,3-dimethyl-1H-indazol-6-yl)-N⁴-methyl-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N⁴-methyl-N² 55 3-[(methylsulfonylmethyl]phenyl}-2,4-pyrimidinediamine;N⁴-(2,3-dimethyl-2H-indazol-6-yl)-N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-methyl-2,4-pyrimidinediamine;1-[4-methoxy-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]-1-propanone;4-methoxy-N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)phenyl]benzenesulfonamide;4-methoxy-N-methyl-3-({4-[(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;[(3-methyl-1H-indazol-6-yl)(2-{4-[(methylsulfonyl)methyl]anilino}-4-pyrimidinyl)amino]acetonitrile;[{2-[5-(ethylsulfonyl)-2-methoxyanilino]-4-pyrimidinyl}(3-methyl-1H-indazol-6-yl)amino]acetonitrile;[(3-methyl-1H-indazol-6-yl)(2-{3-[(methylsulfonyl)methyl]anilino}-4-pyrimidinyl)amino]acetonitrile;4-methoxy-N-methyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzamide;3-methoxy-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;N⁴-ethynyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-{3-[(methylsulfonyl)methyl]phenyl}-2,4-pyrimidinediamine;3-({4-[(3-methyl-1H-indazol-6-yl)(2-propynyl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-[3-(methylsulfonyl)phenyl]-2,4-pyrimidinediamine;4-methoxy-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;N²-[5-(ethylsulfonyl)-2-methoxyphenyl]-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzamide;N²-[4-(ethylsulfonyl)phenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N-[4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzyl]ethanesulfonamide;N-[3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzyl]methanesulfonamide;2-chloro-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;2-chloro-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;4-chloro-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;3-methyl-4-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;2-methyl-5-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;4-methyl-3-({4-[methyl(3-methyl-1H-indazol-6-yl)amino]-2-pyrimidinyl}amino)benzenesulfonamide;N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-N²-[3-(methylsulfinyl)phenyl]-2,4-pyrimidinediamine;N²-[2-fluoro-5-(methylsulfonyl)phenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;N²-[2-methoxy-5-(methylsulfonyl)phenyl]-N⁴-methyl-N⁴-(3-methyl-1H-indazol-6-yl)-2,4-pyrimidinediamine;3-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;2-[4-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)phenyl]ethanesulfonamide;3-({4-[[3-(hydroxymethyl)-2-methyl-2H-indazol-6-yl](methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;3-({4-[(1,2-dimethyl-1H-benzimidazol-5-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide,3-({4-[(2-benzyl-1-methyl-1H-benzimidazol-5-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;3-({4-[(2-ethyl-3-methyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;3-({4-[[2-(3-chlorobenzyl)-3-methyl-2H-indazol-6-yl](methyl)amino]pyrimidin-2-yl}amino)benzenesulfonamide;3-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-1,3,5-triazin-2-yl}amino)benzenesulfonamide;and5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]-1,3,5-triazin-2-yl}amino)-2-methylbenzenesulfonamide;or a salt or thereof. 52-81. (canceled)
 82. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of acompound as claimed in claim 1, or a salt, solvate, or a physiologicallyfunctional derivative thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients.
 83. The pharmaceuticalcomposition of claim 82, further comprising at least one additionalanti-neoplastic agent.
 84. The pharmaceutical composition of claim 82,further comprising an additional agent which inhibits angiogenesis. 85.A method of treating a disorder in a mammal, said disorder beingmediated by inappropriate VEGFR2 activity, comprising: administering tosaid mammal a therapeutically effective amount of a compound as claimedin claim 1, or a salt, solvate, or a physiologically functionalderivative thereof.
 86. The method of claim 85, wherein the disorder iscancer.
 87. A method of treating cancer in a mammal, comprising:administering to said mammal a therapeutically effective amount of acompound as claimed in claim 1, or a salt, solvate, or a physiologicallyfunctional derivative thereof.
 88. The method of claim 87, furthercomprising administering a therapeutically effective amount of at leastone additional anti-cancer therapy.
 89. The method of claim 88, whereinthe additional anti-cancer therapy is administered concomitantly withthe administration of the compound, salt, solvate or physiologicallyfunctional derivative as claimed in claim
 1. 90. The method of claim 88,wherein the additional anti-cancer therapy is administered after theadministration of the compound, salt, solvate or physiologicallyfunctional derivative as claimed in claim
 1. 91. The method of claim 88,wherein the additional anti-cancer therapy is administered before theadministration of the compound, salt, solvate or physiologicallyfunctional derivative as claimed in claim
 1. 92. A method of treating adisorder in a mammal, said disorder being mediated by inappropriateVEGFR2 activity, comprising: administering to said mammaltherapeutically effective amounts of (1) a compound as claimed in claim1, or a salt, solvate or physiologically functional derivative thereofand (ii) an agent to inhibit growth factor receptor function.
 93. Themethod of claim 92, wherein the agent to inhibit growth factor receptorfunction inhibits the function of platelet derived growth factorreceptor.
 94. The method of claim 92, wherein the agent to inhibitgrowth factor receptor function inhibits the function of epidermalgrowth factor receptor.
 95. The method of claim 92, wherein the agent toinhibit growth factor receptor function inhibits the function of theerbB2 receptor.
 96. The method of claim 92, wherein the agent to inhibitgrowth factor receptor function inhibits the function of a VEGFreceptor.
 97. The method of claim 92, wherein the agent to inhibitgrowth factor receptor function inhibits the function of the TIE-2receptor.
 98. The method of claim 92, wherein the agent to inhibitgrowth factor receptor function inhibits the function of the epidermalgrowth factor receptor and erbB2.
 99. The method of claim 92, whereinthe agent to inhibit growth factor receptor function inhibits thefunction of at least two of the epidermal growth factor receptor, erbB2,and erbB4.
 100. The method of claim 92, wherein the agent to inhibitgrowth factor receptor function inhibits the function of the VEGFreceptor and the TIE-2 receptor.
 101. The method of claim 92, whereinthe disorder is cancer.
 102. A method of treating a disorder in amammal, said disorder being characterized by inappropriate angiogenesis,comprising: administering to said mammal a therapeutically effectiveamount of a compound as claimed in claim 1, or a salt, solvate orphysiologically functional derivative thereof.
 103. The method of claim102, wherein the inappropriate angiogenesis results from at least one ofinappropriate VEGFR1, VEGFR2, VEGFR3 or TIE-2 activity.
 104. The methodof claim 102, wherein the inappropriate angiogenesis results frominappropriate VEGFR2 and TIE-2 activity.
 105. The method of claim 102,further comprising administering a therapeutically effective amount of aTIE-2 inhibitor.
 106. The method of claim 102, further comprisingadministering an agent to inhibit growth factor receptor function. 107.The method of claim 102, wherein the disorder is cancer.